Heterocyclic sulfonamide derivatives as antagonists of PAF and angiotensin II

ABSTRACT

Compounds of formula (I), wherein: A represents: a) a --VR 6  group wherein v is --C(═O), --C(═O)O--, --CH 2  O--, --CH 2  OC(═O)--, --C(═S)--, --CH 2  OC(═O)NH--, --C(═S)O--, --CH 2  S--, --C(═O)NHSO 2  --, --SO 2  NHC(═O)-- or --CH 2  OSiPh 2  --; b) a --CH 2  NR 9  R 10  group or a --CONR 9  R 10  group wherein each of R 9  and R 10  is independently hydrogen, -alkyl-, -alkenyl-, -alkynyl, -cycloalkyl, -cycloalkenyl, pyridyl (any of which may optionally be substituted) or a group --D as defined above or R 9  and R 10  together with the nitrogen atom to which they are attached form a nitrogen-containing heterocyclic ring; c) a group Y where Y is a 5- or 6-membered optionally substituted heterocyclic ring containing one or more heteroatoms selected from nitrogen, oxygen and sulphur; or d) a group --CH 2  Y or --C(═O)NHY; where Y is as defined above; B represents a 5- or 6-membered heterocyclic ring containing one or more nitrogen atoms in its ring, are antagonists of platelet activating factor (PAF) and/or antagonists of angiotensin II.

This invention relates primarily to novel substituted amino acidderivatives that possess pharmaceutical activity as antagonists of PAFand/or as antagonists of angiotensin II.

Platelet activating factor (PAF) is a bioactive phospholipid which hasbeen identified as1-O-hexadecyl/octadecyl-2-acetyl-sn-glyceryl-3-phosphoryl choline. PAFis released directly from cell membranes and mediates a range of potentand specific effects on target cells resulting in a variety ofphysiological responses which include hypotension, thrombocytopenia,bronchoconstriction, circulatory shock, and increased vascularpermeability (oedema/erythema). It is known that these physiologicaleffects occur in many inflammatory and allergic diseases and PAF hasbeen found to be involved in a number of such disorders includingasthma, endotoxin shock, adult respiratory distress syndrome,glomerulonephritis, immune regulation, transplant rejection, gastriculceration, psoriasis, and cerebral, myocardial and renal ischemia. Thusthe compounds of the invention, by virtue of their ability to antagonisethe actions of PAF, should be of value in the treatment of any of theabove conditions and any other conditions in which PAF is implicated(e.g. embryo implantation).

Compounds which have been disclosed as possessing activity as PAFantagonists include compounds which are structurally related to the PAFmolecule such as glycerol derivatives (EP-A-0238202), and heterocycliccompounds such as 2,5-diaryl tetrahydrofurans (EP-A-0144804) andimidazopyridine derivatives (EP-A-0260613 and WO-A-8908653).

Angiotensin II is a bioactive octapeptide which is formed fromangiotensin I by the action of angiotensin converting-enzyme.Angiotensin H is a powerful vasopressor agent which has been implicatedas a causative agent of high blood pressure in various mammalianspecies, such as the rat, dog and man. Angiotensin II elevates bloodpressure via binding to specific angiotensin II receptors on cellmembranes. Thus the compounds of the invention, by virtue of theirability to antagonise the actions of angiotensin H, should be of valuein the treatment of elevated blood pressure and congestive heartfailure, glaucoma and intraocular hypertension, cognitive dysfunction,psoriasis and any other conditions in which angiotensin II isimplicated.

Compounds which have been disclosed as possessing activity asangiotensin II antagonists include compounds which are structurallyrelated to the angiotensin II peptide, but the experimental and clinicalapplications of these compounds have been limited by partial agonistactivity (M. A. Ondetti and D. W. Cushman, Annual Reports in MedicinalChemistry, 1978, 13, 82-91). Recently, several non-peptide compoundshave been described as angiotensin II antagonists. Illustrative of suchcompounds are heterocyclic substituted biphenyl derivatives (D. J.Carini et al., J. Med. Chem., 1991, 34, 2525-2547; P. R. Bovy et al.,Med. Chem. Res., 1991, 1, 86-94) and heterocyclic substitutedbenzofurans (EP-A-434,249).

The present invention provides novel and useful substituted sulphonylamino acid derivatives and their pharmaceutically acceptable acidaddition salts, and pharmaceutical uses thereof as PAF antagonists andangiotensin II antagonists.

According to a first aspect of the invention there is provided acompound of general formula I; ##STR1## wherein: A represents:

a) a --VR⁶ group wherein V is --C(═O)--, --C(═O)O--, --CH₂ O--, --CH₂OC(═O)--, --C(═S)--, --CH₂ OC(═O)NH--, --C(═S)O--, --CH₂ S--,--C(═O)NHSO₂ --, --SO₂ NHC(═O)-- or --CH₂ OSiPh₂ --; and

R6 is hydrogen, --C₁ -C₁₈ alkyl, --C₂ -C₁₈ alkenyl, --C₂ -C₁₈ alkynyl,--(C₁ -C₆ alkyl)OC₁ -C₆ alkyl, --(C₁ -C₆ alkyl)SC₁ -C₆ alkyl, --(C₁ -C₆alkyl)O(C₁ -C₆ alkyl)OC₁ -C₆ alkyl, --C₃ -C₈ cycloalkyl, --C₄ -C₈cycloalkenyl or pyridyl, (any of which may optionally be substitutedwith one or more substituents selected from halogen, hydroxyl, nitro,nitrile or carboxyl), C₁ -C₄ perfluoroalkyl, a group --D or a --(C₁ -C₆alkyl)OD group wherein D represents a group ##STR2## wherein n is aninteger from 0 to 3, and each of R⁷ and R⁸ is independently hydrogen,--C₁ -C₆ alkyl, --C₂ -C₆ alkenyl, --C₂ -C₆ alkynyl, halogen, --CN, --CO₂H, --CO₂ C₁ -C₆ alkyl, --CONH₂, --CONHC₁ -C₆ alkyl, --CON(C₁ -C₆alkyl)₂, --CHO, --CH₂ OH, --CF₃, --OC₁ -C₆ alkyl, --SC₁ -C₆ alkyl,--SOC₁ -C₆ alkyl, --SO₂ C₁ -C₆ alkyl, --NH₂ or --NHCOMe;

or a group --CH₂ OSi(R⁶)₃ wherein R⁶ is as defined above;

b) a --CH₂ NR⁹ R¹⁰ group or a --CONR⁹ R¹⁰ group wherein each of R⁹ andR¹⁰ is independently hydrogen, --C₁ -C₁₈ alkyl, --C₂ -C₁₈ alkenyl, --C₂-C₁₈ alkynyl, --C₃ -C₈ cycloalkyl, --C₄ -C₈ cycloalkenyl, pyridyl (anyof which may optionally be substituted with one or more substituentsselected from halogen, hydroxyl, nitro, nitrile or carboxyl) or a group--D as defined above or R⁹ and R¹⁰ together with the nitrogen atom towhich they are attached form a 5 to 8 membered nitrogen-containingheterocyclic ring;

c) a group Y where Y is a 5- or 6-membered heterocyclic ring containingone or more heteroatoms selected from nitrogen, oxygen and sulphur andthe ring may be optionally substituted with one or more substituentsselected from --C₁ -C₆ alkyl, --OC₁ -C₆ alkoxy, halogen, --CF₃ and --CN;or

d) a group --CH₂ --Y or --C(═O)NHY; where Y is as defined above;

R¹ and R² each independently represent hydrogen, halogen, --C₁ -C₆ alkyloptionally substituted by one or more halogen atoms, --C₂ -C₆ alkenyl,--C₂ -C₆ alkynyl, --(C₁ -C₆ alkyl)CO₂ C₁ -C₆ alkyl, --(C₁ -C₆ alkyl)SC₁-C₆ alkyl, --(C₁ -C₆ alkyl)OC₁ -C₆ alkyl, --(C₁ -C₆ alkyl)N(C₁ -C₆alkyl)₂, --C₃ -C₈ cycloalkyl, --C₄ -C₈ cycloalkenyl, --(C₁ -C₆ alkyl)C₃-C₈ cycloalkyl, --(C₁ -C₆ alkyl)C₄ -C₈ cycloalkenyl, --(C₁ -C₆ alkyl)OC₃-C₈ cycloalkyl, --(C₁ -C₆ alkyl)OC₄ -C₈ cycloalkenyl, --(C₁ -C₆alkyl)SC₃ -C₈ cycloalkyl, --(C₁ -C₆ alkyl)SC₄ -C₈ cycloalkenyl, a sidechain of a naturally occurring amino acid, a group --D, or a --(C₁ -C₆alkyl)OD group wherein D is as defined above;

or R¹ and R² together with the carbon atom to which they are attachedform a C₃ -C₈ cycloalkyl ring;

R³ represents hydrogen, --C₁ -C₆ alkyl, --C₂ -C₆ alkenyl, --C₂ -C₆alkynyl, --COC₁ -C₆ alkyl, --CO₂ C₁ -C₆ alkyl, --(COC₁ -C₆ alkyl)phenyl,--(CO₂ C₁ -C₆ alkyl)phenyl, --(C₁ -C₆ alkyl)OC₁ -C₆ alkyl, --(C₁ -C₆alkyl)SC₁ -C₆ alkyl, --(C₁ -C₆ alkyl)CO₂ C₁ -C₆ alkyl, --C₃ -C₈cycloalkyl, --C₄ -C₈ cycloalkenyl or a group --D wherein D is as definedabove;

or R¹ together with R³ and the atoms to which they are attached form a 5to 8 membered nitrogen-containing heterocyclic ring;

R⁴ represents hydrogen, --C₁ -C₆ alkyl, --C₂ -C₆ alkenyl, halogen, --OC₁-C₆ alkyl, --C₁ -C₄ perfluoroalkyl or --C₃ -C₈ cycloalkyl;

R⁵ represents hydrogen, --C₁ -C₆ alkyl, --C₂ -C₆ alkenyl, --C₂ -C₆alkynyl, --CO₂ C₁ -C₆ alkyl, --SC₁ -C₆ alkyl, --(C₁ -C₆ alkyl)SC₁ -C₆alkyl, --(C₁ -C₆ alkyl)OC₁ -C₆ alkyl, --(C₁ -C₆ alkyl)phenyl orthiophenyl;

B represents a 5- or 6-membered heterocyclic ring containing one or morenonquaternised nitrogen atoms in its ring, which heterocyclic ring maybe optionally fused to a benzene ring or to a further 5-, 6- or7-membered heterocyclic ring containing one or more nitrogen atoms,wherein at least one of the said heterocyclic rings may also contain anoxygen or sulphur atom, and wherein any of the rings may be optionallysubstituted with one or more substituents selected from hydrogen,halogen, --C₁ -C₄ perfluoroalkyl, hydroxyl, carbonyl, thiocarbonyl,formyl, carboxyl, --CONH₂, --NO₂, a group --D wherein D is as definedabove, --R¹¹, --OR¹¹, --SR¹¹, --SOR¹¹, --SO₂ R¹¹, --NHR¹¹, --NR¹¹ R¹¹,--CO₂ R¹¹ or --CONHR¹¹ wherein R¹¹ is --C₁ -C₆ alkyl, --C₂ -C₆ alkenyl,--C₂ -C₆ alkynyl, --C₃ -C₈ cycloalkyl or C₄ -C₈ cycloalkenyl each ofwhich is optionally substituted with one or more substituents selectedfrom halogen, hydroxyl, amino, carboxyl, --C₁ -C₄ perfluoroalkyl, --C₁-C₆ alkyl, --C₂ -C₆ alkenyl, --C₂ -C₆ alkynyl, --C₃ -C₈ cycloalkyl, --C₄-C₈ cycloalkenyl, --OC₁ -C₆ alkyl, --SC₁ -C₆ alkyl, tetrazol-5-yl, agroup --D wherein D is as defined above or a heteroaryl orheteroarylmethyl group;

provided that B is other than a substituted or unsubstituted1H-benzimidazoyl, 1-H-imidazo 4,5-c!pyridyl, 3-H-imidazo 4,5-c!pyridylor 5-H-imidazo 4,5-c!pyridyl derivative;

or a pharmaceutically or veterinarily acceptable acid addition salt orhydrate thereof.

Hereafter in this specification the term "compound" includes "salt" or"hydrate" unless the context requires otherwise.

As used herein the term "halogen" or its abbreviation "halo" meansfluoro, chloro, bromo or iodo.

As used herein the term "C₁ -C₆ alkyl" refers to straight chain orbranched chain hydrocarbon groups having from one to six carbon atoms.Illustrative of such alkyl groups are methyl, ethyl, propyl, isopropyl,butyl, isobutyl, sec-butyl, tert-butyl, pentyl, neopentyl and hexyl.

As used herein the term "C₁ -C₁₈ alkyl" refers to straight chain orbranched chain hydrocarbon groups having from one to eighteen carbonatoms. Illustrative of such alkyl groups are methyl, ethyl, propyl,isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, neopentyl,hexyl, decyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl,heptadecyl and octadecyl. From one to six carbon atoms may be preferred.

As used herein the term "C₂ -C₆ alkenyl" refers to straight chain orbranched chain hydrocarbon groups having from two to six carbon atomsand having in addition one double bond, of either E or Z stereochemistrywhere applicable. This term would include for example, vinyl,1-propenyl, 1- and 2-butenyl and 2-methyl-2-propenyl.

As used herein the term "C₂ -C₁₈ alkenyl" refers to straight chain orbranched chain hydrocarbon groups having from two to eighteen carbonatoms and having in addition one or more double bonds, of either E or Zstereochemistry where applicable. This term would include for example,vinyl, 1-propenyl, 1- and 2-butenyl, 2-methyl-2-propenyl, geranyl, andfarnesyl. From two to six carbon atoms may be preferred.

As used herein the term "C₂ -C₆ alkynyl" refers to straight chain orbranched chain hydrocarbon groups having from two to six carbon atomsand having in addition one triple bond. This term would include forexample, ethynyl, 1-propynyl, 1- and 2-butynyl, 2-methyl-2-propynyl,2-pentynyl, 3-pentynyl, 4-pentynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl and5-hexynyl.

As used herein the term "C₂ -C₁₈ alkynyl" refers to straight chain orbranched chain hydrocarbon groups having from two to six carbon atomsand having in addition one triple bond. This term would include forexample, ethynyl, 1-propynyl, 1- and 2-butynyl, 2-methyl-2-propynyl,2-pentynyl, 3-pentynyl, 4-pentynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl,5-hexynyl, 10-undecynyl, 4-ethyl-1-octyn-3-yl, 7-dodecynyl, 9-dodecynyl,10-dodecynyl, 3-methyl-1-dodecyn-3-yl, 2-tridecynyl, 11-tridecynyl,3-tetradecynyl, 7-hexadecynyl and 3-octadecynyl. From two to six carbonatoms may be preferred.

As used herein, the term "C₁ -C₄ perfluoroalkyl" refers to straightchain or branched chain groups having from one to four carbon atoms andsubstituted by more than one fluorine atom. This term would include forexample, trifluoromethyl, 2,2,2-trifluoroethyl, pentafluoroethyl,3,3,3-trifluoro-n-propyl, septafluoro-i-propyl, septafluoro-n-propyl,septafluoro-i-propyl, 4,4,4-trifluoro-n-butyl, nonafluoro-n-butyl,nonafluoro-sec-butyl and nonafluoro-i-butyl.

As used herein the term "OC₁ -C₆ alkyl" refers to straight chain orbranched chain alkoxy groups having from one to six carbon atoms.Illustrative of such alkoxy groups are methoxy, ethoxy, propoxy,isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentoxy,neopentoxy and hexoxy.

As used herein the term "SC₁ -C₆ alkyl" refers to straight chain orbranched chain alkylthio groups having from one to six carbon atoms.Illustrative of such alkyl groups are methylthio, ethylthio, propylthio,isopropylthio, butylthio, isobutylthio, sec-butylthio, tert-butylthio,pentylthio, neopentylthio and hexylthio.

As used herein, the term "C₃ -C₈ cycloalkyl" refers to an alicyclicgroup having from 3 to 8 carbon atoms. Illustrative of such cycloalkylgroups are cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

As used herein, the term "C₄ -C₈ cycloalkenyl" refers to an alicyclicgroup having from 4 to 8 carbon atoms and having in addition one or moredouble bonds. Illustrative of such cycloalkenyl groups arecyclopentenyl, cyclohexenyl, cycloheptenyl and cyclooctenyl.

As used herein, the term "side chain of a naturally occurring aminoacid" includes the side chains of alanine, arginine, asparagine,aspartic acid, cysteine, cystine, glutamic acid, glycine, histidine,5-hydroxylysine, 4-hydroxyproline, isoleucine, leucine, lysine,methionine, phenylalanine, proline, serine, threonine, tryptophan,tyrosine, valine, α-aminoadipic acid, α-amino-n-butyric acid,3,4-dihydroxyphenylalanine, homoserine, α-methylserine, ornithine,pipecolic acid, and thyroxine. The amino acid side chains may beprotected; for example the carboxyl groups of aspartic acid, glutamicacid and α-aminoadipic acid may be esterified (for example as a C₁ -C₆alkyl ester), the amino groups of lysine, ornithine, 5-hydroxylysine,4-hydroxyproline may be converted to amides (for example as a COC₁ -C₆alkyl amide) or carbamates (for example as a C(═O)OC₁ -C₆ alkyl orC(═O)OCH₂ Ph carbamate), the hydroxyl groups of 5-hydroxylysine,4-hydroxyproline, serine, threonine, tyrosine,3,4-dihydroxyphenylalanine, homoserine, α-methylserine and thyroxine maybe converted to ethers (for example a C₁ -C₆ alkyl or a (C₁ -C₆alkyl)phenyl ether) or esters (for example a C(═O)C₁ -C₆ alkyl ester)and the thiol group of cysteine may be converted to thioethers (forexample a C₁ -C₆ alkyl thioether) or thioesters (for example a C(═O)C₁-C₆ alkyl thioester). The stereochemistry at the carbon atom to whichthe amino acid side chain is attached may be either D or L.

As used herein, the term "nitrogen-containing heterocyclic ring" refersto an aromatic or alicyclic ring comprising one or more nitrogen atomsand optionally one or more other heteroatoms. Illustrative of such ringsare pyrrolidine, piperidine, hexamethyleneimine, heptamethyleneimine,morpholine and piperazine.

As used herein, the term "heteroaryl" refers to a 5- or 6-memberedsubstituted or unsubstituted aromatic heterocycle containing one or moreheteroatoms. Illustrative of such rings are thienyl, furyl, imidazolyl,oxadiazolyl, pyridyl, pyrazinyl each of which may be optionallysubstituted by methyl or methoxy.

In compounds of this invention, the presence of several asymmetriccarbon atoms gives rise to diastereoisomers, each of which consists oftwo enantiomers, with the appropriate R or S stereochemistry at eachchiral centre. The invention is understood to include all suchdiastereoisomers, their optically active enantiomers and mixturesthereof.

The term "pharmaceutically or veterinarily acceptable acid additionsalt" refers to a salt prepared by contacting a compound of formula (I)with an acid whose anion is generally considered suitable for human oranimal consumption.

Examples of pharmaceutically and/or veterinarily acceptable acidaddition salts include the hydrochloride, sulphate, phosphate, acetate,propionate, lactate, maleate, succinate and tartrate salts.

It is considered that the main structural features of compounds ofgeneral formula I that are particularly significant in providing theirPAF antagonist activity, are the nitrogen heterocycle (B group) and thesubunit ##STR3## Since it is the presence of the B group and the subunit(i) that appear to be crucial for retention of PAF antagonist activity,there may be considerable variation of the substituent groups R³, and Awithout loss of such activity. Any of the the wide range of substituentsR³ and A defined above may be used with retention of PAF antagonistactivity.

The linkage ##STR4## is considered to function as a spacer element,separating the nitrogen heterocycle from the amino acid subunit. Thenature or identity of the substituents R⁴ and R⁵ therefore is notthought to be particularly critical and any of the wide range ofsubstituents R⁴ and R⁵ specified above may be used with retention of PAFantagonist activity.

It is considered that the main structural features of compounds ofgeneral formula I that are particularly significant in providing theirangiotensin II antagonist activity, are the A group and the B group. TheA group is preferably a carboxylic acid or any one of the groups claimedabove for A that may serve as an acidic isostere (for exampletetrazolyl). The group B is the nitrogen heterocycle and an importantrequirement for angiotensin II activity is that this heterocycle shouldpossess at least one --C₁ -C₆ alkyl group, which is important forproviding a lipophilic interaction with the angiotensin II receptor. Itis understood that other substituents of the group B from the wide rangespecified above may enhance angiotensin II activity. The unit ##STR5##is considered to function as a spacer element, providing an optimalspacial orientation of the B group with respect to the A group. Thenature or identity of the substituents R¹, R², R³, R⁴ and R⁵ thereforeis not thought to be particularly critical and any of the wide range ofsubstituents R¹, R², R³, R⁴ and R⁵ specified above may be used withretention of angiotensin I5I antagonist activity. Although not claimedhere variations of the unit (iii) that involve replacement of the1,4-phenylene group with disubstituted alicyclic, cyclic andheterocyclic moieties are considered likely to result in compounds thatalso possess angiotensin II antagonist activity.

Preferred compounds include those in which, independently or in anycompatible combination:

A represents a VR⁶ group wherein V is a --C(═O)O--, --CH₂ O--, --CH₂OSiPh₂ -- or --C(═O)NHSO₂ -- group and R⁶ represents a hydrogen atom, a--C₁ -C₆ alkyl (for example methyl, ethyl, propyl or t-butyl) group or a--C₁ -C₄ perfluoroalkyl (for example trifluoromethyl) group, or Arepresents a Y group or a --C(═O)NHY group where Y represents atetrazolyl group;

R¹ represents a hydrogen atom, a --C₁ -C₆ alkyl (for example methyl,isopropyl, n-butyl, isobutyl or 2-methylpropyl) group, a --(C₁ -C₆alkyl)CO₂ C₁ -C₆ alkyl (for example ethyl 3-propionate) group, a --(C₁-C₆ alkyl)SC₁ -C₆ alkyl (for example methylthioethylene) group, the sidechain of a naturally occurring amino acid, a group --D or a --(C₁ -C₆alkyl)OD group;

R² represents a hydrogen atom or a --C₁ -C₆ alkyl (for example methyl)group, or together with R¹ and the carbon atom to which they areattached forms a C₃ -C₈ cycloalkyl (for example cyclohexyl) ring;

R³ represents a hydrogen atom or a --C₁ -C₆ alkyl (for example methyl,ethyl or propyl) group;

R⁴ represents a hydrogen atom;

R⁵ represents a hydrogen atom;

n represents an integer of 0 or 1;

R⁷ represents a hydrogen atom or a --OC₁ -C₆ alkyl (for example methoxy)group;

R⁸ represents a hydrogen atom;

B represents a 5- or 6-membered heterocyclic ring selected frompyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl,oxazolyl, pyridyl, pyrimidyl, pyrazinyl or pyridazinyl whichheterocyclic ring may be optionally fused to a benzene ring or to afurther 5-, 6- or 7-membered heterocyclic ring selected from furan,thiophene, pyrrole, imidazole, pyrazole, triazole, tetrazole, thiazole,oxazole, pyridine, pyrimidine, pyrazine, pyridiazine, triazine, azepine,oxazepine, diazepine or thiazepine, wherein any of the rings mayoptionally be substituted with substituents selected from hydrogen,halogen, --C₁ -C₄ perfluoroalkyl, hydroxyl, carbonyl, thiocarbonyl,formyl, carboxyl, --CONH₂, --NO₂, a group --D wherein D is as definedabove, --R¹¹, --OR¹¹, --SR¹¹, --SOR¹¹, SO₂ R¹¹, --NH₂ R¹¹, --NR¹¹R¹¹,CO₂ R¹¹ or CONHR¹¹ wherein R¹¹ is --C₁ -C₆ alkyl, --C₂ -C₆ alkenyl,--C₂ -C₆ alkynyl, --C₃ -C₈ cycloalkyl or --C₄ -C₈ cycloalkenyl, each ofwhich is optionally substituted with one or more substituents selectedfrom halogen , hydroxyl, amino, carboxyl, --C₁ -C₄ perfluoroalkyl, --C₁-C₆ alkyl, --C₂ -C₆ alkenyl, --C₂ -C₆ alkynyl, --C₃ -C₈ cycloalkyl, --C₄-C₈ cycloalkenyl, --OC₁ -C₆ alkyl, --SC₁ -C₆ alkyl, tetrazol-5-yl, agroup --D wherein D is as defined above or a heteroaryl orheteroarylmethyl group;

provided that B is other than a substituted or unsubstituted1H-benzimidazoyl, 1-H-imidazo 4,5-c!pyridyl, 3-H-imidazo 4,5-c!pyridylor 5-H-imidazo 4,5-c!pyridyl derivative.

Particularly preferred compounds are those in which B represents animidazolyl (for example 1-H-imidazolyl, 1-H-2-methylimidazolyl,1-H-2-nitroimidazolyl, 1-H-2-phenylimidazolyl,1-H-2,4-dimethylimidazolyl, 1-H-2,5-dimethylimidazolyl,1-H-4,5-diphenylimidazolyl,1-H-2-n-butyl-4-chloro-5-hydroxymethylimidazolyl,1H-2-n-propyl-4-chloro-5-formylimidazolylmethyl,1H-2on-butyl-4-trifluoromethyl-5-hydroxycarbonylimidazolyl or1H-2-n-butyl-4-chloro-5-(3-methyl-l,2,4-oxadiazol-5-yl)imidazolyl)group, a imidazo 4,5-b!pyridyl (for example 1H-imidazo 4,5-b!pyridyl,3H-imidazo 4,5-b!pyridyl or 3H-2-ethyl-5,7-dimethylimidazo4,5-b!pyridinyl) group, a purinyl (for example 9H-2,6-dichloropurinyl or7H-8-n-butyl-3,7-dihydro-1,3-dimethylpurine-2,6-dionyl) group, a3,7-dihydropurine-2,6-dionyl (for example1H-8-n-butyl-3,7-dihydro-1,3-dimethylpurine-2,6-dionyl) group, a pyrrolo2,3-b!pyridinyl (for example 1H-2-n-propylpyrrolo 2,3-b!pyridinyl)group, a pyrrolo 3,2-c!pyridinyl (for example1H-4-chloro-2,6-dimethylpyrrolo 3,2-c!pyridinyl), a pyrrolo2,3-d!pyrimidin-6-onyl (for example 7H-2,4-dimethyl-5,7-dihydropyrrolo2,3-d!pyrimidin-6-onyl) group, a isoquinol-1-onyl (for example2H-3-n-propylisoquinol-1-onyl) group, a thieno 2,3-d!pyrimidin-4-onyl(for example 3H-2-n-butyl-5-methylthieno 2,3-d!pyrimidin-4-onyl) group,a imidazo 1,2-b!-1,2,4-triazolyl (for example3H-2-n-butyl-6-methyl-5-phenylimidazo 1,2-b!-1,2,4-triazolyl or4H-3on-butyl-5-(4-chlorobenzylthio)-1,2,4-triazolyl) group, a1,2,4-triazolyl (for example 1H-3,5-dibutyl-1,2,4-triazolyl) group, aquinazolin-4-onyl (for example3H-2-n-butyl-6-(1-hydroxy-1-methylethyl)quinazolin-4-onyl) group, a1,2,4-benzothiadiazinedioxide (for example4H-3-ethylthio-1,2,4-benzothiadiazinedioxide) group, a1,6-dihydropyrimidinyl (for example1H-2-n-butyl-4-chloro-1,6-dihydro-5-hydroxycarbonyl-6-methyl-pyrimidinyl)group, a pyrimidin-4-onyl (for example 3H-2-ethylpyrimidin-4-onyl)group, a pyrrolyl (for example 1H-2-n-propylpyrrolyl) group, a pyrido2,3-d!pyrimidin-4-onyl (for example 3H-2-n-butyl-6-methylpyrido2,3-d!pyrimidin-4-onyl) group, a 1,4-dihydo-4-thioxoquinolinyl (forexample 1H-3-n-butyl-1,4-dihydo-4-thioxoquinolinyl) group, or a4-spirocyclopentane-2-imidazoline-5-onyl (for example1H-2-n-butyl-4-spirocyclopentane-2-imidazoline-5-onyl) group.

For PAF receptor antagonist activity R¹ preferably represents the sidechain of the amino acid leucine and R² is a hydrogen atom.

For angiotensin II receptor antagonist activity A preferably representsa --C(═O)OH group, a --C(═O)NHSO₂ C₁ -C₆ alkyl group, a --C(═O)NHSO₂ C₁-C₄ perfluoroalkyl group, a tetrazolyl group or a --C(═O)NHtetrazolylgroup.

Exemplary compounds include:

1. N-4-(1H-2-Phenylimidazolylmethyl)phenylsulphonyl-L-leucine ethylester,

2. N-Methyl-N-4-(1H-2-nitroimidazolylmethyl)phenylsulphonyl-L-leucineethyl ester,

3. N-4-(1H-4,5-Diphenylimidazolylmethyl)phenylsulphonyl-L-leucinyl ethylether,

4.N-4-(1H-2-Butyl-4-chloro-5-hydroxymethylimidazolylmethyl)phenylsulphonyl-L-leucineethyl ester,

5.N-4-(1H-2-Butyl-4-chloro-5-hydroxymethylimidazolylmethyl)phenylsulphonylglycinemethyl ester,

6.N-4-(1H-2-Butyl-4-chloro-5-hydroxymethylimidazolylmethyl)phenylsulphonyl-2,2-dimethylglycinemethyl ester,

7.N-4-(1H-2-Butyl-4-chloro-5-hydroxymethylimidazolylmethyl)phenylsulphonyl-1-methoxycarbonylcyclohexylamine,

8.N-4-(1H-2-Butyl-4-chloro-5-hydroxymethylimidazolylmethyl)phenylsulphonyl-D,L-alaninemethyl ester,

9.N-4-(1H-2-Butyl-4-chloro-5-hydroxymethylimidazolylmethyl)phenylsulphonyl-D-phenylalaninemethyl ester,

10.N-4-(1H-2-Butyl-4-chloro-5-hydroxymethylimidazolylmethyl)phenylsulphonyl-L-phenylalaninemethyl ester,

1.N-4-(1H-2-Butyl-4-chloro-5-hydroxymethylimidazolylmethyl)phenylsulphonyl-L-valinemethyl ester,

12.N-4-(1H-2-Butyl-4-chloro-5-hydroxymethylimidazolylmethyl)phenylsulphonyl-D-valinemethyl ester,

13.N-4-(1H-2-Butyl-4-chloro-5-hydroxymethylimidazolylmethyl)phenylsulphonyl-D,L-t-butylglycinemethyl ester,

14.N-4-(1H-2-Butyl-4-chloro-5-hydroxymethylimidazolylmethyl)phenylsulphonyl-D-leucineethyl ester,

15.N-4-(1H-2-Butyl-4-chloro-5-hydroxymethylimidazolylmethyl)phenylsulphonyl-L-isoleucineethyl ester,

16.N-4-(1H-2-Butyl-4-chloro-5-hydroxymethylimidazolylmethyl)phenylsulphonyl-D-isoleucineethyl ester,

17.N-4-(1H-2-Butyl-4-chloro-5-hydroxymethylimidazolylmethyl)phenylsulphonyl-D,L-norleucineethyl ester,

18.N-4-(1H-2-Butyl-4-chloro-5-hydroxymethylimidazolylmethyl)phenylsulphonyl-O-methyl-L-tyrosinemethyl ester,

19.N-4-(1H-2-Butyl-4-chloro-5-hydroxymethylimidazolylmethyl)phenylsulphonyl-O-methyl-D-tyrosinemethyl ester,

20.N-4-(1H-2-Butyl-4-chloro-5-hydroxymethylimidazolylmethyl)phenylsulphonyl-O-benzyl-D,L-serinemethyl ester,

21.N-4-(1H-2-Butyl-4-chloro-5-hydroxymethylimidazolylmethyl)phenylsulphonyl-D,L-methioninemethyl ester,

22.N-4-(1H-2-Butyl-4-chloro-5-hydroxymethylimidazolylmethyl)phenylsulphonyl-D,L-asparticacid diethyl ester,

23.N-Methyl-N-4-(1H-2-butyl-4-chloro-5-hydroxymethylimidazolylmethyl)phenylsulphonyl-L-leucineethyl ester,

24.N-Methyl-N-4-(1H-2-butyl-4-chloro-5-hydroxymethylimidazolylmethyl)phenylsulphonyl-L-leucinen-propyl ester,

25.N-Methyl-N-4-(1H-2-butyl-4-chloro-5-hydroxymethylimidazolylmethyl)phenylsulphonylglycinemethyl ester,

26.N-Methyl-N-4-(1H-2-butyl-4-chloro-5-hydroxymethylimidazolylmethyl)phenylsulphonyl-2,2-dimethylglycinemethyl ester,

27.N-Methyl-N-4-(1H-2-butyl-4-chloro-5-hydroxymethylimidazolylmethyl)phenylsulphonyl-1-methoxycarbonylcyclohexylamine,

28.N-Methyl-N-4-(1H-2-butyl-4-chloro-5-hydroxymethylimidazolylmethyl)phenylsulphonyl-D,L-alaninemethyl ester,

29.N-Ethyl-N-4-(1H-2-butyl-4-chloro-5-hydroxymethylimidazolylmethyl)phenylsulphonyl-D-phenylalaninemethyl ester,

30.N-Ethyl-N-4-(1H-2-butyl-4-chloro-5-hydroxymethylimidazolylmethyl)phenylsulphonyl-L-phenylalaninemethyl ester,

31.N-Methyl-N-4-(1H-2-butyl-4-chloro-5-hydroxymethylimidazolylmethyl)phenylsulphonyl-L-valinemethyl ester,

32.N-Methyl-N-4-(1H-2-butyl-4-chloro-5-hydroxymethylimidazolylmethyl)phenylsulphonyl-D-valinemethyl ester,

33.N-Methyl-N-4-(1H-2-butyl-4-chloro-5-hydroxymethylimidazolylmethyl)phenylsulphonyl-D,L-t-butylglycinemethyl ester,

34.N-Methyl-N-4-(1H-2-butyl-4-chloro-5-hydroxymethylimidazolylmethyl)phenylsulphonyl-D-leucineethyl ester,

35.N-n-Propyl-N-4-(1H-2-butyl-4-chloro-5-hydroxymethylimidazolylmethyl)phenylsulphonyl-L-isoleucineethyl ester,

36.N-n-Propyl-N-4-(1H-2-butyl-4-chloro-5-hydroxymethylimidazolylmethyl)phenylsulphonyl-D-isoleucineethyl ester,

37.N-Methyl-N-4-(1H-2-butyl-4-chloro-5-hydroxymethylimidazolylmethyl)phenylsulphonyl-D,L-norleucineethyl ester,

38.N-Methyl-N-4-(1H-2-butyl-4-chloro-5-hydroxymethylimidazolylmethyl)phenylsulphonyl-O-methyl-L-tyrosinemethyl ester,

39.N-Methyl-N-4-(1H-2-butyl-4-chloro-5-hydroxymethylimidazolylmethyl)phenylsulphonyl-O-methyl-D-tyrosinemethyl ester,

40.N-Methyl-N-4-(1H-2-butyl-4-chloro-5-hydroxymethylimidazolylmethyl)phenylsulphonyl-O-benzyl-D,L-serinemethyl ester,

41.N-Methyl-N-4-(1H-2-butyl-4-chloro-5-hydroxymethylimidazolylmethyl)phenylsulphonyl-D,L-methioninemethyl ester,

42.N-Methyl-N-4-(1H-2-butyl-4-chloro-5-hydroxymethylimidazolylmethyl)phenylsulphonyl-D,L-asparticacid diethyl ester,

43. N-Methyl-N-4-(1H-2-ethylimidazolylmethyl)phenylsulphonyl-L-leucinemethyl ester,

44.N-Methyl-N-4-(1H-2-n-propylimidazolylmethyl)phenylsulphonyl-L-leucinemethyl ester,

45. (A) N-4-(3H-Imidazo 4,5-b!pyridylmethyl)phenylsulphonyl-L-leucinylethyl ether, (B) N-4-(1H-Imidazo4,5-b!pyridylmethyl)phenylsulphonyl-L-leucinyl ethyl ether,

46. N-4-(1H-2-n-Propylpyrrolo2,3-b!pyridinylmethyl)phenylsulphonylglycine methyl ester,

47.N-4-(2H-3-n-Propylisoquinol-1-onylmethyl)phenylsulphonyl-2,2-dimethylglycinemethyl ester,

48. N-4-(3H-2-n-Butyl-5-methylthieno2,3-d!pyrimidin-4-onylmethyl)phenylsulphonyl-1-methoxycarbonylcyclohexylamine,49. N-4-(3H-2-n-Butyl-6-methyl-5-phenylimidazo1,2-b!-1,2,4-triazolylmethyl)-phenylsulphonyl-D,L-alanine methyl ester,

50. N-4-(1H-4-Chloro-2,6-dimethylpyrrolo3,2-c!pyridinylmethyl)phenylsulphonyl-L-phenylalanine methyl ester,

51. N-4-(1H-4-Chloro-2,6-dimethylpyrrolo3,2-c!pyridinylmethyl)phenylsulphonyl-D-phenylalanine methyl ester,

52.N-4-(7H-8-n-Butyl-3,7-dihydro-1,3-dimethylpurine-2,6-dionylmethyl)phenylsulphonyl-L-phenylalaninemethyl ester,

53.N-4-(7H-8-n-Butyl-3,7-dihydro-1,3-dimethylpurine-2,6-dionylmethyl)phenylsulphonyl-L-phenylalaninemethyl ester,

54. N-4-(1H-3,5-Dibutyl-1,2,4-triazolylmethyl)phenylsulphonyl-L-valinemethyl ester,

55. N-4-(1H-3,5-Dibutyl-1,2,4-triazolylmethyl)phenylsulphonyl-D-valinemethyl ester,

56.N-4-(3H-2-n-Butyl-6-(1-hydroxy-1-methylethyl)quinazolin-4-onylmethyl)phenylsulphonyl-D,L-t-butylglycinemethyl ester,

57. N-4-(7H-2,4-Dimethyl-5,7-dihydropyrrolo2,3-d!pyrimidin-6-onylmethyl)phenylsulphonyl-L-leucine ethyl ester,

58. N-4-(7H-2,4-Dimethyl-5,7-dihydropyrrolo2,3-d!pyrimidin-6-onylmethyl)phenylsulphonyl-D-leucine ethyl ester,

59.N-4-(1H-2-n-Propyl-4-chloro-5-formylimidazolylmethyl)phenylsulphonyl-L-isoleucineethyl ester,

60.N-4-(1H-2-n-Propyl-4-chloro-5-formylimidazolylmethyl)phenylsulphonyl-D-isoleucineethyl ester,

61. N-Methyl-N-4-(3H-2-ethyl-5,7-dimethylimidazo4,5-b!pyridinylmethyl)phenylsulphonylglycine methyl ester,

62. N-Methyl-N-4-(3H-2-ethyl-5,7-dimethylimidazo4,5-b!pyridinylmethyl)phenylsulphonyl-2,2-dimethylglycine methyl ester,

63. N-Methyl-N-4-(3H-2-ethyl-5,7-dimethylimidazo4,5-b!pyridinylmethyl)phenylsulphonyl-1-methoxycarbonylcyclohexylamine,

64. N-Methyl-N-4-(3H-2-ethyl-5,7-dimethylimidazo4,5-b!pyridinylmethyl)phenylsulphonyl-D,L-alanine methyl ester,

65. N-4-(3H-2-Ethyl-5,7-dimethylimidazo4,5-b!pyridinylmethyl)phenylsulphonyl-D,L-alanine methyl ester,

66. N-Methyl-N-4-(3H-2-ethyl-5,7-dimethylimidazo4,5-b!pyridinylmethyl)phenylsulphonyl-D,L-alanine methyl ester,

67.N-Methyl-N-4-(4H-3-ethylthio-1,2,4-benzothiadiazinedioxidemethyl)phenylsulphonyl-D-phenylalaninemethyl ester,

68.N-Methyl-N-4-(4H-3-ethylthio-1,2,4-benzothiadiazinedioxidemethyl)phenylsulphonyl-L-phenylalaninemethyl ester,

69.N-Methyl-N-4-(4H-3-n-butyl-5-(4-chlorobenzylthio)-1,2,4-triazolylmethyl)phenylsulphonyl-L-valinemethyl ester,

70.N-Methyl-N-4-(4H-3-n-butyl-5-(4-chlorobenzylthio)-1,2,4-triazolylmethyl)phenylsulphonyl-D-valinemethyl ester,

71.N-Methyl-N-4-(1H-2-n-butyl-4-chloro-1,6-dihydro-5-hydroxycarbonyl-6-methylpyrimidinylmethyl)phenylsulphonyl-D,L-t-butylglycinemethyl ester,

72.N-Methyl-N-4-(1H-2-n-butyl-4-trifluoromethyl-5-hydroxycarbonylimidazolylmethyl)phenylsulphonyl-D-leucineethyl ester,

73.N-Methyl-N-4-(1H-2-n-butyl-4-trifluoromethyl-5-hydroxycarbonylimidazolylmethyl)phenylsulphonyl-L-leucineethyl ester,

74.N-Methyl-N-4-(3H-2-ethylpyrimidin-4-onylmethyl)phenylsulphonyl-L-isoleucineethyl ester,

75.N-Methyl-N-4-(3H-2-ethylpyrimidin-4-onylmethyl)phenylsulphonyl-D-isoleucineethyl ester,

76.N-Methyl-N-4-(1H-2-n-propylpyrrolylmethyl)phenylsulphonyl-D,L-norleucineethyl ester,

77. N-Methyl-N-4-(3H-2-n-butyl-6-methylpyrido2,3-d!pyrimidin-4-onylmethyl)phenylsulphonyl-O-methyl-L-tyrosine methylester,

78. N-Methyl-N-4-(3H-2-n-butyl-6-methylpyrido2,3-d!pyrimidin-4-onylmethyl)phenylsulphonyl-O-methyl-D-tyrosine methylester,

79.N-Methyl-N-4-(1H-3-n-butyl-1,4-dihydo-4-thioxoquinolinylmethyl)phenylsulphonyl-O-benzyl-D,L-serinemethyl ester,

80.N-Methyl-N-4-(1H-2-n-butyl-4-chloro-5-(3-methyl-1,2,4-oxadiazol-5-yl)imidazolylmethyl)-phenylsulphonyl-D,L-methioninemethyl ester,

81.N-Methyl-N-4-(1H-2-n-butyl-4-spirocyclopentane-2-imidazoline-5-onylmethyl)phenylsulphonyl-D,L-asparticacid diethyl ester,

82. N-Methyl-N-4-(9H-2,6-dichloropurinylmethyl)phenylsulphonyl-L-leucinen-propyl ester,

83. N-4-(1H-Imidazolylmethyl)phenylsulphonyl-L-leucinylt-butyldiphenylsilyl ether,

84. N-4-(1H-Imidazolylmethyl)phenylsulphonyl-L-leucinol,

85. N-4-(1H-2-Methylimidazolylmethyl)phenylsulphonyl-L-leucinol,

86.N-Methyl-N-4-(1H-2-butyl-4-chloro-5-hydroxymethylimidazolylmethyl)phenylsulphonyl-L-leucine,

87. N-Methyl-N-4-(1H-2-ethylimidazolylmethyl)phenylsulphonyl-L-leucine,

88.N-Methyl-N-4-(1H-2-n-propylimidazolylmethyl)phenylsulphonyl-L-leucine,

89.N-4-(1H-2-Butyl-4-chloro-5-hydroxymethylimidazolylmethyl)phenylsulphonylglycine,

90.N-4-(1H-2-Butyl-4-chloro-5-hydroxymethylimidazolylmethyl)phenylsulphonyl-2,2-dimethylglycine,

91.N-4-(1H-2-Butyl-4-chloro-5-hydroxymethylimidazolylmethyl)phenylsulphonyl-1-aminocyclohexanecarboxylicacid,

92.N-4-(1H-2-Butyl-4-chloro-5-hydroxymethylimidazolylmethyl)phenylsulphonyl-D,L-alanine,

93.N-4-(1H-2-Butyl-4-chloro-5-hydroxymethylimidazolylmethyl)phenylsulphonyl-D-phenylalanine,

94.N-4-(1H-2-Butyl-4-chloro-5-hydroxymethylimidazolylmethyl)phenylsulphonyl-L-phenylalanine,

95.N-4-(1H-2-Butyl-4-chloro-5-hydroxymethylimidazolylmethyl)phenylsulphonyl-L-valine,

96.N-4-(1H-2-Butyl-4-chloro-5-hydroxymethylimidazolylmethyl)phenylsulphonyl-D-valine,

97.N-4-(1H-2-Butyl-4-chloro-5-hydroxymethylimidazolylmethyl)phenylsulphonyl-D,L-t-butylglycine,

98.N-4-(1H-2-Butyl-4-chloro-5-hydroxymethylimidazolylmethyl)phenylsulphonyl-D-leucine,

99.N-4-(1H-2-Butyl-4-chloro-5-hydroxymethylimidazolylmethyl)phenylsulphonyl-D-leucine,

100.N-4-(1H-2-Butyl-4-chloro-5-hydroxymethylimidazolylmethyl)phenylsulphonyl-L-isoleucine,

101.N-4-(1H-2-Butyl-4-chloro-5-hydroxymethylimidazolylmethyl)phenylsulphonyl-D-isoleucine,

102.N-4-(1H-2-Butyl-4-chloro-5-hydroxymethylimidazolylmethyl)phenylsulphonyl-D,L-norleucine,

103.N-4-(1H-2-Butyl-4-chloro-5-hydroxymethylimidazolylmethyl)phenylsulphonyl-O-methyl-L-tyrosine,

104.N-4-(1H-2-Butyl-4-chloro-5-hydroxymethylimidazolylmethyl)phenylsulphonyl-O-methyl-D-tyrosine,

105.N-4-(1H-2-Butyl-4-chloro-5-hydroxymethylimidazolylmethyl)phenylsulphonyl-O-benzyl-D,L-serine,

106.N-4-(1H-2-Butyl-4-chloro-5-hydroxymethylimidazolylmethyl)phenylsulphonyl-D,L-methionine,

107.N-4-(1H-2-Butyl-4-chloro-5-hydroxymethylimidazolylmethyl)phenylsulphonyl-D,L-asparticacid,

108.N-Methyl-N-4-(1H-2-butyl-4-chloro-5-hydroxymethylimidazolylmethyl)phenylsulphonylglycine,

109.N-Methyl-N-4-(1H-2-butyl-4-chloro-5-hydroxymethylimidazolylmethyl)phenylsulphonyl-2,2-dimethylglycine,

110.N-Methyl-N-4-(1H-2-butyl-4-chloro-5-hydroxymethylimidazolylmethyl)phenylsulphonyl-1-aminocyclohexanecarboxylicacid,

111.N-Methyl-N-4-(1H-2-butyl-4-chloro-5-hydroxymethylimidazolylmethyl)phenylsulphonyl-D,L-alanine,

112.N-Ethyl-N-4-(1H-2-butyl-4-chloro-5-hydroxymethylimidazolylmethyl)phenylsulphonyl-D-phenylalanine,

113.N-Ethyl-N-4-(1H-2-butyl-4-chloro-5-hydroxymethylimidazolylmethyl)phenylsulphonyl-L-phenylalanine,

114.N-Methyl-N-4-(1H-2-butyl-4-chloro-5-hydroxymethylimidazolylmethyl)phenylsulphonyl-L-valine,

115.N-Methyl-N-4-(1H-2-butyl-4-chloro-5-hydroxymethylimidazolylmethyl)phenylsulphonyl-D-valine,

116.N-Methyl-N-4-(1H-2-butyl-4-chloro-5-hydroxymethylimidazolylmethyl)phenylsulphonyl-D,L-t-butylglycine,

117.N-Methyl-N-4-(1H-2-butyl-4-chloro-5-hydroxymethylimidazolylmethyl)phenylsulphonyl-L-leucine,

118.N-Methyl-N-4-(1H-2-butyl-4-chloro-5-hydroxymethylimidazolylmethyl)phenylsulphonyl-D-leucine,

119. N-n-Propyl-N-4-(1H-2-butyl-4-chloro-5-hydroxymethylimidazolylmethyl)phenylsulphonyl-L-isoleucine,

120.N-n-Propyl-N-4-(1H-2-butyl-4-chloro-5-hydroxymethylimidazolylmethyl)phenylsulphonyl-D-isoleucine,

121.N-Methyl-N-4-(1H-2-butyl-4-chloro-5-hydroxymethylimidazolylmethyl)phenylsulphonyl-D,L-norleucine,

122.N-Methyl-N-4-(1H-2-butyl-4-chloro-5-hydroxymethyIimidazolylmethyl)phenylsulphonyl-O-methyl-L-tyrosine,

123.N-Methyl-N-4-(1H-2-butyl-4-chloro-5-hydroxymethylimidazolylmethyl)phenylsulphonyl-O-methyl-D-tyrosine,

124.N-Methyl-N-4-(1H-2-butyl-4-chloro-5-hydroxymethylimidazolylmethyl)phenylsulphonyl-O-benzyl-D,L-serine,

125.N-Methyl-N-4-(1H-2-butyl-4-chloro-5-hydroxymethylimidazolylmethyl)phenylsulphonyl-D,L-methionine,

126.N-Methyl-N-4-(1H-2-butyl-4-chloro-5-hydroxymethylimidazolylmethyl)phenylsulphonyl-D,L-asparticacid,

127. N-4-(1H-2-n-Propylpyrrolo2,3-b!pyridinylmethyl)phenylsulphonylglycine,

128.N-4-(2H-3-n-Propylisoquinol-1-onylmethyl)phenylsulphonyl-2,2-dimethylglycine,

129. N-4-(3H-2-n-Butyl-5-methylthieno2,3-d!pyrimidin-4-onylmethyl)phenylsulphonyl-1-aminocyclohexanecarboxylicacid,

130. N-4-(3H-2-n-Butyl-6-methyl-5-phenylimidazo1,2-b!-1,2,4-triazolylmethyl)phenylsulphonyl-D,L-alanine,

131. N-4-(1H-4-Chloro-2,6-dimethylpyrrolo3,2-c!pyridinylmethyl)phenylsulphonyl-L-phenylalanine,

132. N-4-(1H-4-Chloro-2,6-dimethylpyrrolo3,2-c!pyridinylmethyl)phenylsulphonyl-D-phenylalanine,

133.N-4-(7H-8-n-Butyl-3,7-dihydro-1,3-dimethylpurine-2,6-dionylmethyl)phenylsulphonyl-L-phenylalanine,

134.N-4-(7H-8-n-Butyl-3,7-dihydro-1,3-dimethylpurine-2,6-dionylmethyl)phenylsulphonyl-D-phenylalanine,

135. N-4-(1H-3,5-Dibutyl-1,2,4-triazolylmethyl)phenylsulphonyl-L-valine,

136. N-4-(1H-3,5-Dibutyl-1,2,4-triazolylmethyl)phenylsulphonyl-D-valine,

137.N-4-(3H-2-n-Butyl-6-(1-hydroxy-1-methylethyl)quinazolin-4-onylmethyl)phenylsulphonyl-D,L-t-butylglycine,

138. N-4-(7H-2,4-Dimethyl-5,7-dihydropyrrolo2,3-d!pyrimidin-6-onylmethyl)phenylsulphonyl-L-leucine,

139. N-4-(7H-2,4-Dimethyl-5,7-dihydropyrrolo2,3-d!pyrimidin-6-onylmethyl)phenylsulphonyl-D-leucine,

140.N-4-(1H-2-n-Propyl-4-chloro-5-formylimidazolylmethyl)phenylsulphonyl-L-isoleucine,

141.N-4-(1H-2-n-Propyl-4-chloro-5-formylimidazolylmethyl)phenylsulphonyl-D-isoleucine,

142. N-Methyl-N-4-(3H-2-ethyl-5,7-dimethylimidazo4,5-b!pyridinylmethyl)phenylsulphonylglycine,

143. N-Methyl-N-4-(3H-2-ethyl-5,7-dimethylimidazo4,5-b!pyridinylmethyl)phenylsulphonyl-2,2-dimethylglycine,

144. N-Methyl-N-4-(3H-2-ethyl-5,7-dimethylimidazo4,5-b!pyridinylmethyl)phenylsulphonyl-1-aminocyclohexanecarboxylic acid,

145. N-Methyl-N-4-(3H-2-ethyl-5,7-dimethylimidazo4,5-b!pyridinylmethyl)phenylsulphonyl-D,L-alanine,

146. N-4-(3H -2-Ethyl-5,7-dimethylimidazo4,5-b!pyridinylmethyl)phenylsulphonyl-D,L-alanine,

147. N-Methyl-N-4-(3H-2-ethyl-5,7-dimethylimidazo4,5-b!pyridinylmethyl)phenylsulphonyl-D,L-alanine,

148.N-Methyl-N-4-(4H-3-ethylthio-1,2,4-benzothiadiazinedioxidemethyl)phenylsulphonyl-D-phenylalanine,

149.N-Methyl-N-4-(4H-3-ethylthio-1,2,4-benzothiadiazinedioxidemethyl)phenylsulphonyl-L-phenylalanine,

150.N-Methyl-N-4-(4H-3-n-butyl-5-(4-chlorobenzylthio)-1,2,4-triazolylmethyl)phenylsulphonyl-L-valine,

151.N-Methyl-N-4-(4H-3-n-butyl-5-(4-chlorobenzylthio)-1,2,4-triazolylmethyl)phenylsulphonyl-D-valine,

152.N-Methyl-N-4-(1H-2-n-butyl-4-chloro-1,6-dihydro-5-hydroxycarbonyl-6-methylpyrimidinylmethyl)phenylsulphonyl-D,L-t-butylglycine,

153.N-Methyl-N-4-(1H-2-n-butyl-4-trifluoromethyl-5-hydroxycarbonylimidazolylmethyl)phenylsulphonyl-D-leucine,

154.N-Methyl-N-4-(1H-2-n-butyl-4-trifluoromethyl-5-hydroxycarbonylimidazolylmethyl)phenylsulphonyl-L-leucine,

155.N-Methyl-N-4-(3H-2-ethylpyrimidin-4-onylmethyl)phenylsulphonyl-L-isoleucine,

156.N-Methyl-N-4-(3H-2-ethylpyrimidin-4-onylmethyl)phenylsulphonyl-D-isoleucine,

157.N-Methyl-N-4-(1H-2-n-propylpyrrolylmethyl)phenylsulphonyl-D,L-norleucine,

158. N-Methyl-N-4-(3H-2-n-butyl-6-methylpyrido2,3-d!pyrimidin-4-onylmethyl)phenylsulphonyl-0-methyl-L-tyrosine,

159. N-Methyl-N-4-(3H-2-n-butyl-6-methylpyrido2,3-d!pyrimidin-4-onylmethyl)phenylsulphonyl-0-methyl-D-tyrosine,

160.N-Methyl-N-4-(1H-3-n-butyl-1,4-dihydo-4-thioxoquinolinylmethyl)phenylsulphonyl-O-benzyl-D,L-serine,

161.N-Methyl-N-4-(1H-2-n-butyl-4-chloro-5-(3-methyl-1,2,4-oxadiazol-5-yl)imidazolylmethyl)-phenylsulphonyl-D,L-methionine,

162.N-Methyl-N-4-(1H-2-n-butyl-4-spirocyclopentane-2-imidazoline-5-onylmethyl)phenylsulphonyl-D,L-asparticacid,

163.N-4-(1H-2-Butyl-4-chloro-5-hydroxymethylimidazolylmethyl)phenylsulphonyl-1-(1H-tetrazol-5-yl)methylamine,

164.N-Methyl-N-4-(1H-2-butyl-4-chloro-5-hydroxymethylimidazolylmethyl)phenylsulphonyl-1-methyl-1-(1H-tetrazol-5-yl)ethylamine,

165.N-Methyl-N-4-(1H-2-butyl-4-chloro-5-hydroxymethylimidazolylmethyl)phenylsulphonyl-1-(1H-tetrazol-5-yl)cyclohexylamine,

166.(S)-N-4-(1H-3,5-Dibutyl-1,2,4-triazolylmethyl)phenylsulphonyl-2-methyl-1-(1H-tetrazol-5-yl)propylamine,

167.(R)-N-4-(1H-3,5-Dibutyl-1,2,4-triazolylmethyl)phenylsulphonyl-2-methyl-1-(1H-tetrazol-5-yl)propylamine,

168.(S)-N-4-(1H-2-Butyl-4-chloro-5-formylimidazolylmethyl)phenylsulphonyl-2-methyl-1-(1H-tetrazol-5-yl)butylamine,

169.(R)-N-4-(1H-2-Butyl-4-chloro-5-formylimidazolylmethyl)phenylsulphonyl-2-methyl-1-(1H-tetrazol-5-yl)butylamine,

170.N-Methyl-N-4-(1H-2-n-butyl-4-chloro-1,6-dihydro-5-hydroxycarbonyl-6-methylpyrimidinylmethyl)phenylsulphonyl-2,2-dimethyl-1-(1H-tetrazol-5-yl)propylamine,

171.N-Methyl-N-4-(1H-2-butyl-4-chloro-5-hydroxymethylimidazolylmethyl)phenylsulphonyl-1-(1H-tetrazol-5-yl)ethylamine,

172.(S)-N-Ethyl-N-4-(1H-2-butyl-4-chloro-5-hydroxymethylimidazolylmethyl)phenylsulphonyl-1-phenyl-1-(1H-tetrazol-5-yl)methylamine,

173.(R)-N-Ethyl-N-4-(1H-2-butyl-4-chloro-5-hydroxymethylimidazolylmethyl)phenylsulphonyl-1-phenyl-1-(1H-tetrazol-5-yl)methylamine,

174.(S)-N-Methyl-N-4-(1H-2-butyl-4-chloro-5-hydroxymethylimidazolylmethyl)phenylsulphonyl-1-methyl-1-(1H-tetrazol-5-yl)ethylamine,

175.(R)-N-Methyl-N-4-(1H-2-butyl-4-chloro-5-hydroxymethylimidazolylmethyl)phenylsulphonyl-1-methyl-1-(1H-tetrazol-5-yl)ethylamine,

176.N-Methyl-N-4-(1H-2-butyl-4-chloro-5-hydroxymethylimidazolylmethyl)phenylsulphonyl-2,2-dimethyl-1-(1H-tetrazol-5-yl)-propylamine,

177.N-4-(1H-2-Butyl-4-chloro-5-hydroxymethylimidazolylmethyl)phenylsulphonylglycine1H-tetrazol-5-ylamide,

178.N-4-(1H-2-Butyl-4-chloro-5-hydroxymethylimidazolylmethyl)phenylsulphonyl-2,2-dimethylglycine1H-tetrazol-5-ylamide,

179.N-4-(1H-2-Butyl-4-chloro-5-hydroxymethylimidazolylmethyl)phenylsulphonyl-D,L-alanine1H-tetrazol-5-ylamide,

180.N-4-(1H-2-Butyl-4-chloro-5-hydroxymethylimidazolylmethyl)phenylsulphonyl-D-phenylalanine1H-tetrazol-5-ylamide,

181.N-4-(1H-2-Butyl-4-chloro-5-hydroxymethylimidazolylmethyl)phenylsulphonyl-L-phenylalanine1H-tetrazol-5-ylamide,

182.N-4-(1H-2-Butyl-4-chloro-5-hydroxymethylimidazolylmethyl)phenylsulphonyl-L-valinetrifluoromethylsulphonylamide,

183.N-4-(1H-2-Butyl-4-chloro-5-hydroxymethylimidazolylmethyl)phenylsulphonyl-D-valinetrifluoromethylsulphonylamide,

184.N-4-(1H-2-Butyl-4-chloro-5-hydroxymethylimidazolylmethyl)phenylsulphonyl-D,L-t-butylglycine1H-tetrazol-5-ylamide,

185.N-4-(1H-2-Butyl-4-chloro-5-hydroxymethylimidazolylmethyl)phenylsulphonyl-D-leucinemethylsulphonylamide,

186.N-4-(1H-2-Butyl-4-chloro-5-hydroxymethylimidazolylmethyl)phenylsulphonyl-D-leucinemethylsulphonylamide,

187. N-Methyl-N-4-(3H-2-ethyl-5,7-dimethylimidazo4,5-b!pyridinylmethyl)phenylsulphonylglycine 1H-tetrazol-5-ylamide,

188. N-Methyl-N-4-(3H -2-ethyl-5,7-dimethylimidazo4,5-b!pyridinylmethyl)phenylsulphonyl-2,2-dimethylglycine1H-tetrazol-5-ylamide,

189. N-Methyl-N-4-(3H-2-ethyl-5,7-dimethylimidazo4,5-b!pyridinylmethyl)phenylsulphonyl-D,L-alanine 1H-tetrazol-5-ylamide,

190. N-4-(3H-2-Ethyl-5,7-dimethylimidazo4,5-b!pyridinylmethyl)phenylsulphonyl-D,L-alanine 1H-tetrazol-5-ylamide,

191. N-Methyl-N-4-(3H-2-ethyl-5,7-dimethylimidazo4,5-b!pyridinylmethyl)phenylsulphonyl-D,L-alanine 1H-tetrazol-5-ylamide,

192.N-Methyl-N-4-(4H-3-ethylthio-1,2,4-benzothiadiazinedioxidemethyl)phenylsulphonyl-D-phenylalaninetrifluoromethylsulphonylamide,

193.N-Methyl-N-4-(4H-3-ethylthio-1,2,4-benzothiadiazinedioxidemethyl)phenylsulphonyl-L-phenylalaninetrifluoromethylsulphonylamide,

194.N-Methyl-N-4-(1H-2-butyl-4-chloro-5-hydroxymethylimidazolylmethyl)phenylsulphonylglycine1H-tetrazol-5-ylamide,

195.N-Methyl-N-4-(1H-2-butyl-4-chloro-5-hydroxymethylimidazolylmethyl)phenylsulphonyl-2,2-dimethylglycine1H-tetrazol-5-ylamide,

196.N-Methyl-N-4-(1H-2-butyl-4-chloro-5-hydroxymethylimidazolylmethyl)phenylsulphonyl-D,L-alanine1H-tetrazol-5-ylamide,

197.N-Ethyl-N-4-(1H-2-butyl-4-chloro-5-hydroxymethylimidazolylmethyl)phenylsulphonyl-D-phenylalanine1H-tetrazol-5-ylamide,

198.N-Ethyl-N-4-(1H-2-butyl-4-chloro-5-hydroxymethylimidazolylmethyl)phenylsulphonyl-L-phenylalanine1H-tetrazol-5-ylamide,

199.N-Methyl-N-4-(1H-2-butyl-4-chloro-5-hydroxymethylimidazolylmethyl)phenylsulphonyl-L-valinetrifluoromethylsulphonylamide,

200.N-Methyl-N-4-(1H-2-butyl-4-chloro-5-hydroxymethylimidazolylmethyl)phenylsulphonyl-D-valinetrifluoromethylsulphonylamide,

201.N-Methyl-N-4-(1H-2-butyl-4-chloro-5-hydroxymethylimidazolylmethyl)phenylsulphonyl-D,L-t-butylglycinetrifluoromethylsulphonylamide,

202.N-Methyl-N-4-(1H-2-butyl-4-chloro-5-hydroxymethylimidazolylmethyl)phenylsulphonyl-L-leucine1H-tetrazol-5-ylamide,

203.N-Methyl-N-4-(1H-2-butyl-4-chloro-5-hydroxymethylimidazolylmethyl)phenylsulphonyl-D-leucine1H-tetrazol-5-ylamide.

Compounds of general formula I may be prepared by any suitable methodknown in the art and/or by the following process, which itself formspart of the invention.

According to a second aspect of the invention, there is provided aprocess for preparing a compound of general formula I as defined above,the process comprising:

(a) treating a compound represented by general formula II

    BH                                                         II

wherein B is as defined in general formula I, with a suitable base (e.g.sodium hydride, potassium hydride, sodium bis(trimethylsilyl)amide,potassium hydroxide or sodium methoxide), followed by a compound ofgeneral formula III ##STR6## wherein R¹, R², R³, R⁴, R⁵ and A are asdefined in general formula I, and L is a leaving group such as chloro,bromo, iodo, methanesulphonyloxy, p-toluenesulphonyloxy ortrifluoromethanesulphonyloxy; or

(b) optionally after step (a), converting, in one or a plurality ofsteps, a compound of general formula I into another compound of generalformula I.

The reaction of step (a) can for preference be conducted in an aproticsolvent (e.g. tetrahydrofuran, N,N-dimethylformamide or acetonitrile) toyield compounds of general formula I. In the case where anunsymmetrically substituted derivative B is used the reaction can yieldan isomeric mixture, which is separated by chromatography to yieldcompounds of general formula I.

By means of step (b), compounds of general formula I wherein A is a--CO₂ R⁶ group can be convened to compounds of general formula I inwhich A is a --CO₂ H group by acid or base catalysed hydrolysis in aprotic solvent. Suitable acids for use in the hydrolysis includesulphuric and hydrochloric acids, whilst base hydrolysis can becatalysed with sodium or potassium hydroxide.

If A represents a --CO₂ R⁶ group in which R⁶ is a benzyl group, theconversion of A from an ester to an acid can also be effected byhydrogenation in a suitable solvent, for example, a lower alcohol suchas ethanol using a noble metal catalyst such as palladium or platinum.

Also by means of step (b), compounds of general formula I in which A isa --CO₂ R⁶ group can be convened to compounds of general formula I inwhich A represents a --CH₂ OH group by reduction using any suitablemethod although lithium aluminium hydride or diisobutyl aluminiumhydride in an aprotic solvent such as diethyl ether or toluene haveproved to be particularly appropriate reducing agents.

Also by means of step (b), compounds of general formula I wherein A is a--C(═O)NHY or --C(═O)NR⁹ R¹⁰ group wherein Y, R⁹ and R¹⁰ are as definedfor general formula I, may be prepared by treatment of a compound ofgeneral formula I wherein A is --CO₂ R⁶ wherein R⁶ is hydrogen bytreatment with an amine of general formula H₂ NY or HNR⁹ R¹⁰ in thepresence of a coupling reagent (e.g. 1,3-dicyclohexylcarbodiimide).

Also by means of step (b), compounds of general formula I wherein A is a--C(═O)NHSO₂ R⁶ wherein R⁶ is as defined for general formula I, may beprepared by activation of a compound of general I wherein A is --CO₂ R⁶wherein R⁶ is hydrogen by conversion to the acid chloride or acylimidazole followed by treatment with an alkali metal salt of asulphonamide of general formula H₂ NSO₂ R⁶.

Also by means of step (b), compounds of general formula I wherein A is agroup Y wherein Y is a tetrazol-5-yl group may be prepared by thetreatment of a compound of general I wherein A is --C(═O)NR⁹ R¹⁰ groupwherein R⁹ is hydrogen and R¹⁰ is --CH₂ CH₂ CN with triphenylphosphine,diethyl azodicarboxylate and azidotrimethylsilane according to theprocedure described by V. Duncia, M. E. Pierce and J. B. Santella III,J. Org. Chem., 1991, 56, 2395-2400.

Derivatives of general formula II are generally available or may beprepared by a number of methods known to those skilled in the art.

Compounds of general formula III may be prepared by treatment of anamine of general formula IV ##STR7## wherein R¹, R², R³ and A are asdefined in general formula I, with a sulphonyl halide of general formulaV ##STR8## wherein R⁴ and R⁵ are as defined in general formula I, L is aleaving group such as chloro, bromo, iodo, methanesulphonyloxy,p-toluenesulphonyloxy or trifluoromethanesulphonyloxy and Hal is ahalide (e.g. fluoro, chloro or bromo), in the presence of a suitablebase (e.g. triethylamine). Amines of general formula IV and sulphonylhalides of general formula V are known in the art or may be prepared bymethods known in the art.

The appropriate solvents employed in the above reactions are solventswherein the reactants are soluble but do not react with the reactants.The preferred solvents vary from reaction to reaction and are readilyascertained by one of ordinary skill in the art.

Compounds of general formula III are valuable intermediates in thepreparation of compounds of general formula I, as are other novelcompounds specifically or generically disclosed herein. Therefore,according to a third aspect of the invention, there is provided acompound of general formula III.

Compounds of general formula I are potentially useful both as PAFantagonists and as antagonists of angiotensin II.

This invention also relates to methods of treatment for patients (oranimals including mammalian animals raised in the dairy, meat, or furtrades, or as pets) suffering from disorders or diseases which can beattributed to PAF or to angiotensin II as previously described. Morespecifically, the invention relates to a method of treatment involvingthe administration of PAF antagonists of general formula I as the activeingredient and also to a method of treatment involving theadministration of angiotensin II antagonists of general formula I as theactive ingredient. In addition to the treatment of warm blooded animalssuch as mice, rats, horses, cattle, pigs, sheep, dogs, cats, etc., thecompounds of the invention are effective in the treatment of humans.

According to a fourth aspect of the invention there is provided acompound of general formula I for use in human or veterinary medicineparticularly in the management of diseases mediated by PAF or byangiotensin II. When used as PAF antagonists, the compounds of generalformula I can be used among other things to reduce inflammation andpain, to correct respiratory, cardiovascular, and intravascularalterations or disorders, and to regulate the activation or coagulationof platelets, to correct hypotension during shock, the pathogenesis ofimmune complex deposition and smooth muscle contractions. When used asangiotensin II antagonists, the compounds of general formula I can beused in the treatment of conditions such as hypertension, congestiveheart failure, glaucoma and intraocular hypertension, cognitivedysfunction and psoriasis although they also have potential in thetreatment of other conditions.

According to a fifth aspect of the invention there is provided the useof a compound of general formula I in the preparation of an agent forthe treatment or prophylaxis of PAF-mediated diseases, and/or thetreatment of inflammatory disorders such as rheumatoid arthritis,osteoarthritis and eye inflammation, cardiovascular disorder,thrombocytopenia, asthma, endotoxin shock, adult respiratory distresssyndrome, glomerulonephritis, immune regulation, gastric ulceration,transplant rejection, psoriasis, allergic dermatitis, urticaria,multiple sclerosis, cerebral, myocardial and renal ischemia and anyother condition in which PAF is implicated.

According to a further aspect of the invention, there is provided theuse of a compound of general formula I in the preparation of an agentfor the treatment or prophylaxis of diseases and conditions mediated byangiotensin II. This includes the preparation of an agent for thetreatment of the conditions mentioned above, particularly elevated bloodpressure.

Compounds of general formula (I) may be administered orally, topically,parenterally, by inhalation spray or rectally in dosage unitformulations containing conventional non-toxic pharmaceuticallyacceptable carriers, adjuvants and vehicles. The term parenteral as usedherein includes subcutaneous injections, intravenous, intramuscular,intrasternal injection or infusion techniques.

According to yet another aspect of the invention there is provided apharmaceutical or veterinary formulation comprising a compound ofgeneral formula I and a pharmaceutically and/or veterinarily acceptablecarder. One or more compounds of general formula I may be present inassociation with one or more non-toxic pharmaceutically and/orveterinarily acceptable carders and/or diluents and/or adjuvants and ifdesired other active ingredients. The pharmaceutical compositionscontaining compounds of general formula I may be in a form suitable fororal use, for example, as tablets, troches, lozenges, aqueous or oilysuspensions, dispersible powders or granules, emulsions, hard or softcapsules, or syrups or elixirs.

Compositions intended for oral use may be prepared according to anymethod known to the art for the manufacture of pharmaceuticalcompositions and such compositions may contain one or more agentsselected from the group consisting of sweetening agents, flavouringagents, colouring agents and preserving agents in order to providepharmaceutically elegant and palatable preparations. Tablets contain theactive ingredient in admixture with non-toxic pharmaceuticallyacceptable excipients which are suitable for the manufacture of tablets.These excipients may be for example, inert diluents, such as calciumcarbonate, sodium carbonate, lactose, calcium phosphate or sodiumphosphate; granulating and disintegrating agents, for example, cornstarch, or alginic acid; binding agents, for example starch, gelatin oracacia, and lubricating agents, for example magnesium stearate, stearicacid or talc. The tablets may be uncoated or they may be coated by knowntechniques to delay disintegration and absorption in thegastrointestinal tract and thereby provide a sustained action over alonger period. For example, a time delay material such as glycerylmonostearate or glyceryl distearate may be employed.

Formulations for oral use may also be presented as hard gelatin capsuleswherein the active ingredient is mixed with an inert solid diluent, forexample, calcium carbonate, calcium phosphate or kaolin, or as softgelatin capsules wherein the active ingredient is mixed with water or anoil medium, for example peanut oil, liquid paraffin, or olive oil.

Aqueous suspensions contain the active materials in admixture withexcipients suitable for the manufacture of aqueous suspensions. Suchexcipients are suspending agents, for example sodiumcarboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose,sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia;dispersing or wetting agents may be a naturally-occuring phosphatide,for example lecithin, or condensation products of an alkylene oxide withfatty acids for example polyoxyethylene stearate, or condensationproducts of ethylene oxide with long chain aliphatic alcohols, forexample heptadecaethyleneoxycetanol, or condensation products ofethylene oxide with partial esters derived from fatty acids and ahexitol such as polyoxyethylene sorbitol monooleate, or condensationproducts of ethylene oxide with partial esters derived from fatty acidsand hexitol anhydrides, for example polyethylene sorbitan monooleate.The aqueous suspensions may also contain one or more preservatives, forexample ethyl, or n-propyl p-hydroxybenzoate, one or more colouringagents, one or more flavouring agents, and one or more sweeteningagents, such as sucrose or saccharin.

Oily suspensions may be formulated by suspending the active ingredientsin a vegetable oil, for example arachis oil, olive oil, sesame oil orcoconut oil, or in a mineral oil such as liquid paraffin. The oilysuspensions may contain a thickening agent, for example beeswax, hardparaffin or cetyl alcohol. Sweetening agents such as those set forthabove, and flavouring agents may be added to provide a palatable oralpreparations. These compositions may be preserved by the addition of ananti-oxidant such as ascorbic acid.

Dispersible powders and granules suitable for preparation of an aqueoussuspension by the addition of water provide the active ingredient inadmixture with a dispersing or wetting agent, suspending agent and oneor more preservatives. Suitable dispersing or wetting agents andsuspending agents are exemplified by those already mentioned above.Additional excipients, for example sweetening, flavouring and colouringagents, may also be present.

Pharmaceutical compositions of the invention may also be in the form ofoil-in-water emulsions. The oily phase may be a vegetable oil, forexample olive oil or arachis oil, or a mineral oil, for example liquidparaffin or mixtures of these. Suitable emulsifying agents may benaturally-occurring gums, for example gum acacia or gum tragacanth,naturally-occurring phosphatides, for example soy bean, lecithin, andesters or partial esters derived from fatty acids and hexitolanhydrides, for example sorbitan monooleate, and condensation productsof the said partial esters with ethylene oxide, for examplepolyoxyethylene sorbitan monooleate. The emulsions may also containsweetening and flavouring agents.

Syrups and elixirs may be formulated with sweetening agents, for exampleglycerol, propylene glycol, sorbitol or sucrose. Such formulations mayalso contain a demulcent, a preservative and flavouring and colouringagents. The pharmaceutical compositions may be in the form of a sterileinjectable aqueous or oleaginous suspension. This suspension may beformulated according to the known art using those suitable dispersing orwetting agents and suspending agents which have been mentioned above.The sterile injectable preparation may also be a sterile injectablesolution or suspension in a non-toxic parentally acceptable diluent orsolvent, for example as a solution in 1,3-butane diol. Among theacceptable vehicles and solvents that may be employed are water,Ringer's solution and isotonic sodium chloride solution. In addition,sterile, fixed oils are conventionally employed as a solvent orsuspending medium. For this purpose any bland fixed oil may be employedincluding synthetic mono- or diglycerides. In addition, fatty acids suchas oleic acid find use in the preparation of injectables.

The compounds of general formula I may also be administered in the formof suppositories for rectal administration of the drug. Thesecompositions can be prepared by mixing the drug with a suitablenon-irritating excipient which is solid at ordinary temperatures butliquid at the rectal temperature and will therefore melt in the rectumto release the drug. Such materials are cocoa butter and polyethyleneglycols.

For topical application to the skin compounds of general formula I maybe made up into a cream, ointment, jelly, solution or suspension etc.Cream or ointment formulations that may be used for the drug areconventional formulations well known in the art, for example, asdescribed in standard text books of pharmaceutics such as the BritishPharmacopoeia.

For topical applications to the eye, compounds of general formula I maybe made up into a solution or suspension in a suitable sterile aqueousor non-aqueous vehicle. Additives, for instance buffers, preservativesincluding bactericidal and fungicidal agents, such as phenyl mercuricacetate or nitrate, benzalkonium chloride or chlorohexidine, andthickening agents such as hypromellose may also be included.

Compounds of general formula I may be administered parenterally in asterile medium. The drug, depending on the vehicle and concentrationused, can either be suspended or dissolved in the vehicle.Advantageously, adjuvants such as a local anaesthetic, preservative andbuffering agents can be dissolved in the vehicle.

Compounds of general formula I may be used for the treatment of therespiratory tract by nasal or buccal administration of, for example,aerosols or sprays which can disperse the pharmacologically activeingredient, in the form of a powder or in the form of drops of asolution or suspension. Pharmaceutical compositions withpowder-dispersing properties usually contain, in addition to the activeingredient, a liquid propellant with a boiling point below roomtemperature and, if desired, adjuncts, such as liquid or solid nonionicor anionic surfactants and/or diluents. Pharmaceutical compositions inwhich the pharmacologically active ingredient is in solution contain, inaddition to this, a suitable propellant, and furthermore, if necessary,an additional solvent and/or a stabiliser. Instead of the propellant,compressed air can also be used, it being possible for this to beproduced as required by means of a suitable compression and expansiondevice.

Dosage levels of the order of from about 0.1 mg to about 140 mg perkilogram of body weight per day are useful in the treatment of theabove-indicated conditions (about 0.5 mg to about 7 g per patient perday). For example, inflammation may be effectively treated by theadministration of from about 0.01 to 50 mg of the compound per kilogramof body weight per day (about 1.0 mg to about 3.5 g per patient perday). The dosage employed for the topical administration will, ofcourse, depend on the size of the area being treated. For the eyes eachdose will be typically in the range from 10 to 100 mg of the drug.

The amount of active ingredient that may be combined with the carriermaterials to produce a single dosage form will vary depending upon thehost treated and the particular mode of administration. For example, aformulation intended for the oral administration of humans may containfrom 0.5 mg to 5 g of active agent compounded with an appropriate andconvenient amount of carder material which may vary from about 5 toabout 95 percent of the total composition. Dosage unit forms willgenerally contain between from about 1 mg to about 500 mg of an activeingredient.

It will be understood, however, that the specific dose level for anyparticular patient will depend upon a variety of factors including theactivity of the specific compound employed, the age, body weight,general health, sex, diet, time of administration, route ofadministration, rate of excretion, drug combination and the severity ofthe particular disease undergoing therapy.

It has been found that the compounds of general formula I exhibit invitro antagonistic activities with respect to PAF and to angiotensin II.Compounds of general formula I inhibit PAF-induced and angiotensin Hinduced functions in both the cellular and tissue levels by changing thePAF binding to its specific receptor site and the binding of angiotensinII to its specific receptor. The ability of compounds of general formulaI to inhibit the binding of PAF to its specific receptor binding site onhuman platelet plasma membranes was measured according to Example 204.The angiotensin II antagonist activity of compounds of general formula Iis demonstrated in vitro by their ability to inhibit the contraction ofrabbit aorta rings caused by angiotensin II was measured according toExample 205. The attached drawing FIG. 1, shows inhibition ofangiotensin II induced contraction of rabbit aorta rings.

The following examples illustrate the invention, but are not intended tolimit the scope in any way.

The following abbreviations have been used in the Examples:

DCM-Dichloromethane

DIPE-Diisopropylether

DMF-N,N-Dimethylformamide

NBS-N-Bromosuccinimide

TDA-1-Tris(2-(2-methoxyethoxy)ethyl)amine

THF-Tetrahydrofuran

Unless otherwise stated ¹ H NMR and ¹³ C NMR spectra were recorded on aBruker AC-250 spectrometer at 250 MHz and 62.9 MHz respectively usingCDCl₃ as a solvent and internal reference and are reported as delta ppmfrom TMS.

EXAMPLE 1

N-4-(1H-2-Phenylimidazolylmethyl)phenylsulphonyl-L-leucine ethyl ester##STR9## (a) 4-Bromomethylphenylsulphonylchloride

To a solution of p-toluenesulphonyl chloride (50 g, 0.26 mol) in benzene(150 ml) and NBS (46.7 g, 0.26 mol) heated at reflux was added2,2'-azobis(2-methylpropionitrile) (100 mg). The mixture was heated atreflux for 12 h and allowed to cool to room temperature. The whiteprecipitate of succinimide that formed was separated and discarded. Thefiltrate was taken up in DCM (200 ml) and washed with water (3×100 ml)followed by brine (100 ml) and dried over anhydrous sodium sulphate.Filtration, concentration and subsequent crystallisation (from DIPE)gave in two crops 4-bromomethylphenylsulphonylchloride (46.3 g, 66%) asa white crystalline solid.

m.p. 75°-76° C.

delta_(H) 8.02 (2H, d, J 8.5 Hz), 7.64 (2H, d, J 8.5 Hz), 4.52 (2H, s).

(b) N-4-Bromomethylphenylsulphonyl-L-leucine ethyl ester

L-leucine ethyl ester hydrochloride (75.0 g. 0.403 mol) was suspended inTHF (300 ml) at 0° C., and triethylamine (67 ml, 0.484 mol) addedslowly. After stirring for 15 mins a solution of 4-bromomethylsulphonylchloride (108.4 g, 0.403 mol) in THF (100 ml) was added via cannula. Thereaction mixture was allowed to stir overnight at ambient temperature.The solvent was removed under low pressure and the organics wereextracted into ethyl acetate (200 ml) and washed with water (100 ml) andbrine (100 ml). The organic portion was dried over anhydrous magnesiumsulphate, filtered and the solvent evaporated under low pressure. Theproduct was recrystallised from DIPE (500 ml) to giveN-4-bromomethylphenylsulphonyl-L-leucine ethyl ester (134g, 85%) as awhite crystalline solid.

delta_(H) 7.84 (2H, d, J 8.3 Hz), 7.52 (2H, d, J 8.3 Hz), 5.06 (1H, d, J10.1 Hz), 4.61 (2H, s), 3.97-3.82 (3H, m), 1.85-1.79 (1H, m), 1.49 (2H,t, J 7.1 Hz), 1.08 (3H, t, J 7.1 Hz), 0.92 (3H, d, J 6.7 Hz), 0.91 (3H,d, J 6.5 Hz).

(c) N-4-(1H-2-Phenylimidazolylmethyl)phenylsulphonyl-L-leucine ethylester

Sodium hydride (60% dispersion in oil: 197 mg, 4.92 mmol) was added to astirred solution of 2-phenylimidazole (710 mg, 4.92 mmol) in dry THF (60ml) under argon at room temperature. After 2 h a solution ofN-4-bromomethylphenylsulphonyl-L-leucine ethyl ester (2.0 g, 4.92 mmol)in dry THF (60 ml) was added. The mixture was stirred for 8 h andsaturated ammonium chloride (200 ml) was added and the product extractedwith ethyl acetate (3×150 ml). The combined organic layers were washedwith water (2×100 ml), dried over anhydrous sodium sulphate, filteredand the solvent removed. Chromatography (silica: 5% methanol in DCM)gave N-4-(1H-2-phenylimidazolylmethyl)phenylsulphonyl-L-leucine ethylester (1.0 g, 45%) as a white foam.

Analysis calculated for C₂₄ H₂₉ N₃ O₄ S.0.5H₂ O Requires C 62.05 H 6.51N 9.04 Found C 62.06 H 6.30 N 9.18

i.r. (CDCl₃) 1730, 1340, 1155 cm⁻¹

delta_(H) 7.76 (2H, d, J 8.3 Hz), 7.50-7.42 (2H, m), 7.40-7.32 (3H, m),7.19 (1H, d, J 1.3 Hz), 7.12 (2H, d, J 8.3 Hz), 6.93 (1H, d, J 1.0 Hz),5.90 (1H, d, J 9.9 Hz), 5.26 (2H, s), 3.95-3.72 (3H, m), 1.80-1.62 (1H,m), 1.50-1.38 (2H, m), 1.03 (3H, t, J 7.2 Hz), 0.84 (3H, d, J 5.2 Hz),0.81 (3H, d, J 5.0 Hz).

EXAMPLE 2

N-Methyl-N-4-(1H-2-nitroimidazolylmethyl)phenylsulphonyl-L-leucine ethylester ##STR10## (a) N-Methyl-N-4-bromomethylphenylsulphonyl-L-leucineethyl ester

N-4-Bromomethylphenylsulphonyl-L-leucine ethyl ester (2.0 g, 5.1 mmol)was dissolved in dry THF (30 ml) under argon and cooled to 0° C. Sodiumhydride (60% dispersion in oil: 200 mg, 5.1 mmol) was added followed bymethyl iodide (0.64 ml, 10.2 mmol) after a period of 5 mins. Thereaction mixture was allowed to warm to room temperature and was stirredovernight. The reaction mixture was quenched with saturated aqueousammonium chloride (30 ml) and extracted with ethyl acetate (2×50 ml).The combined organic extracts were washed with brine (50 ml), dried overanhydrous sodium sulphate, filtered and evaporated to giveN-methyl-N-4-bromomethylphenylsulphonyl-L-leucine ethyl ester as anorange oil which was used directly in the next step without furtherpurification.

delta_(H) 7.81 (2H, d, J 8.5 Hz), 7.52 (2H, d, J 8.5 Hz), 4.66 (1H, dd,J 9.3, 7.4 Hz), 4.62 (2H, s), 3.99-3.79 (2H, m), 2.87 (3H, s), 1.74-1.58(3H, m), 1.07 (3H, t, J 7.3 Hz), 0.99 (3H, d, J 5.2 Hz), 0.97 (3H, d, H,J 6.0 Hz).

(b) N-Methyl-N-4-(1H-2-nitroimidazolylmethyl)phenylsulphonyl-L-leucineethyl ester

A solution of 1M sodium bis(trimethylsilyl)amide (4.42 ml, 4.42 mmol)was added to a stirred solution of 2-nitroimidazole (500 mg, 4.42 mmol)in a mixture of dry THF (50 ml) and dry DMF (5 ml) at room temperatureunder argon. After 15 min a solution ofN-methyl-N-4-bromomethylphenylsulphonyl-L-leucine ethyl ester (1.80 g,4.42 mmol) in dry THF (10 ml) was added and the reaction mixture wasstirred at room temperature overnight. The solvent was removed underreduced pressure and the residue was extracted into ethyl acetate andwashed with aqueous ammonium chloride, brine, dried over anhydroussodium sulphate, filtered and evaporated. Chromatography (silica: 2%methanol in DCM) gaveN-methyl-N-4-(1H-2-nitroimidazolylmethyl)phenylsulphonyl-L-leucine ethylester (0.39 g, 73%) as a pale yellow oil.

i.r. (CDCl₃) 2960, 1730, 1540, 1480, 1335, 1155 cm-1

delta_(H) 7.57 (2H, d, J 8.4 Hz), 7.23 (1H, d, J 0.7 Hz), 7.15 (2H, d, J8.3 Hz), 7.03 (1H, d, J 0.8 Hz), 5.56 (2H, s), 4.44 (1H, t, J 6.7 Hz),3.66 (2H, m), 2.68 (3H, s), 1.45 (3H, m), 0.97-0.78 (9H, m);

delta_(C) 169.20, 143.03, 138.17, 137.61, 129.92, 127.76, 127.16,126.38, 126.09, 125.50, 59.48, 55.78, 51.09, 36.50, 28.39, 22.85, 21.48,19.57, 12.34.

EXAMPLE 3

N-4-(1H-4,5-Diphenylimidazolylmethyl)phenylsulphonyl-L-leucinyl ethylether ##STR11## (a) L-Leucinyl ethyl ester

Sodium hydride (60% dispersion in oil: 4.5 g, 0.11 mol) was added to astirred solution of L-leucinol (12.8 ml, 0.10 mol) in a mixture of dryacetonitrile (24 ml) and dry THF (200 ml) at room temperature underargon. The mixture was heated at reflux for 2 h, cooled to 55° C. andethyl iodide (8.2 ml, 0.10 mol) added carefully. The reaction mixturewas heated at reflux overnight and allowed to cool to room temperature.Ice cold brine (100 ml) was added carefully and the mixture extractedwith ethyl acetate (3×100 ml). The combined organic extracts were driedover anhydrous sodium sulphate, filtered and evaporated. The residue wasdistilled under reduced pressure to give L-leucinyl ethyl ether (4.5 g,30%) as a colourless oil which was used directly in the next step.

delta_(H) 3.49-3.14 (4H, m), 3.08-2.81 (2H, m), 1.73-1.50 (1H, m),1.16-0.91 (6H, m), 0.84 (3H, d, J 6.9 Hz), 0.81 (3H, d, J 6.7 Hz).

(b) N-4-Bromomethylphenylsulphonyl-L-leucinyl ethyl ether

N-4-Bromomethylphenylsulphonyl-L-leucinyl ethyl ether was prepared bythe procedure described in Example 1 Step (b) employing L-leucinyl ethylether in lieu of L-leucine ethyl ester hydrochloride.

White crystalline solid (68% yield): m.p. 70° C.

i.r. (CDCl₃) 3380, 2960, 2870, 1410, 1365, 1155, 1115 cm⁻¹

delta_(H) 7.85 (2H, d, J 8.4 Hz), 7.49 (2H, d, J 8.3 Hz), 5.02 (1H, d, J8.4 Hz), 4.48 (2H, s), 3.47-3.20 (5H, m), 1.56 (1H, m), 1.45-1.20 (2H,m), 1.04 (3H, t, J 7.0 Hz), 0.82 (3H, d, J 6.6 Hz), 0.74 (3H, d, J 6.5Hz).

(c) N-4-(1H-4,5-Diphenylimidazolylmethyl)phenylsulphonyl-L-leucinylethyl ether

N-4-(1H-4,5-Diphenylimidazolylmethyl)phenylsulphonyl-L-leucinyl ethylether was prepared by the procedure of Example 1 Step (c) employing4,5-diphenylimidazole in lieu of 2-phenylimidazole andN-4-bromomethylphenylsulphonyl-L-leucinyl ethyl ether in lieu ofN-4-bromomethylphenylsulphonyl-L-leucine ethyl ester.

Colourless oil (5% yield for last step after chromatography (silica: 3%methanol in DCM)):

i.r. (CDCl₃)2210, 1605, 1410, 1335, 1120 cm⁻¹

delta_(H) 7.78 (2H, d, J 8.4 Hz), 7.54-7.29 (6H, m), 7.16-7.10 (5H, m),7.04 (2H, d, J 8.3 Hz), 5.16 (1H, d, J 8.4 Hz), 5.05 (2H, s), 3.48-3.10(5H, m), 1.54-1.20 (3H, m), 1.05 (3H, t, J 7.0 Hz), 0.82 (3H, d, J 6.5Hz), 0.75 (3H, d, J 6.5 Hz);

delta_(C) 141.23, 141.08, 137.04, 134.07, 130.72, 130.02, 129.00,128.90, 128.56, 128.12, 127.89, 127.46, 127.08, 126.50, 71.81, 66.51,51.95, 48.09, 41.63, 24.28, 22.75, 21.91, 14.86.

EXAMPLE 4

N-4-(1H-2-Butyl-4-chloro-5-hydroxymethylimidazolylmethyl)phenylsulphonyl-L-leucineethyl ester ##STR12##N-4-(1H-2-Butyl-4-chloro-5-hydroxymethylimidazolylmethyl)phenylsulphonyl-L-leucineethyl ester was prepared by the procedure of Example 2 Step (b)employing 2-butyl-4-chloro-5-hydroxymethylimidazole in lieu of2-nitroimidazole and N-4-bromomethylphenylsulphonyl-L-leucine ethylester in lieu of N-methyl-N-4-bromomethylphenylsulphonyl-L-leucine ethylester. 2-Butyl-4-chloro-5-hydroxymethylimidazole was prepared by theprocedure described in U.S. Pat. No. 4,355,040.

Colourless oil (30% yield for last step after chromatography (silica: 5%methanol in DCM)):

i.r. (CDCl₃) 1730, 1340, 1150 cm⁻¹

delta_(H) 7.80 (2H, d, J 8.3 Hz), 7.11 (2H, d, J 8.3 Hz), 5.41 (1H, d, J10.0 Hz), 5.14 (2H, s), 4.58 (2H, s), 3.98-3.78 (3H, m), 2.56 (2H, dd, J8.2, 7.4 Hz), 1.83-1.52 (3H, m), 1.47 (2H, m), 1.40-1.25 (2H, m), 1.07(3H, t, J 7.2 Hz), 0.91-0.80 (9H, m);

delta_(C) 172.09, 148.09, 140.66, 139.69, 135.41, 127.96, 126.49,113.99, 61.45, 55.96, 54.39, 46.41, 42.22, 29.63, 27.30, 24.25, 22.65,22.29, 21.31, 13.89.

EXAMPLES 5-22

The compounds of Examples 5-22 may be prepared by the procedures ofExample 1 Step (b) and Example 4 employing the appropriate amino acidderivative as starting material in lieu of L-leucine ethyl esterhydrochloride.

5.N-4-(1H-2-Butyl-4-chloro-5-hydroxymethylimidazolylmethyl)phenylsulphonylglycinemethyl ester

6.N-4-(1H-2-Butyl-4-chloro-5-hydroxymethylimidazolylmethyl)phenylsulphonyl-2,2-dimethylglycinemethyl ester

7.N-4-(1H-2-Butyl-4-chloro-5-hydroxymethylimidazolylmethyl)phenylsulphonyl-1-methoxycarbonylcyclohexylamine

8.N-4-(1H-2-Butyl-4-chloro-5-hydroxymethylimidazolylmethyl)phenylsulphonyl-D,L-alaninemethyl ester

9.N-4-(1H-2-Butyl-4-chloro-5-hydroxymethylimidazolylmethyl)phenylsulphonyl-D-phenylalaninemethyl ester

10.N-4-(1H-2-Butyl-4-chloro-5-hydroxymethylimidazolylmethyl)phenylsulphonyl-L-phenylalaninemethyl ester

11.N-4-(1H-2-Butyl-4-chloro-5-hydroxymethylimidazolylmethyl)phenylsulphonyl-L-valinemethyl ester

12.N-4-(1H-2-Butyl-4-chloro-5-hydroxymethylimidazolylmethyl)phenylsulphonyl-D-valinemethyl ester

13.N-4-(1H-2-Butyl-4-chloro-5-hydroxymethylimidazolylmethyl)phenylsulphonyl-D,L-t-butylglycinemethyl ester

14.N-4-(1H-2-Butyl-4-chloro-5-hydroxymethylimidazolylmethyl)phenylsulphonyl-D-leucineethyl ester

15.N-4-(1H-2-Butyl-4-chloro-5-hydroxymethylimidazolylmethyl)phenylsulphonyl-L-isoleucineethyl ester

16.N-4-(1H-2-Butyl-4-chloro-5-hydroxymethylimidazolylmethyl)phenylsulphonyl-D-isoleucineethyl ester

17.N-4-(1H-2-Butyl-4-chloro-5-hydroxymethylimidazolylmethyl)phenylsulphonyl-D,L-norleucineethyl ester

18.N-4-(1H-2-Butyl-4-chloro-5-hydroxymethylimidazolylmethyl)phenylsulphonyl-O-methyl-L-tyrosinemethyl ester

19.N-4-(1H-2-Butyl-4-chloro-5-hydroxymethylimidazolylmethyl)phenylsulphonyl-O-methyl-D-tyrosinemethyl ester

20.N-4-(1H-2-Butyl-4-chloro-5-hydroxymethylimidazolylmethyl)phenylsulphonyl-O-benzyl-D,L-serinemethyl ester

21.N-4-(1H-2-Butyl-4-chloro-5-hydroxymethylimidazolylmethyl)phenylsulphonyl-D,L-methioninemethyl ester

22.N-4-(1H-2-Butyl-4-chloro-5-hydroxymethylimidazolylmethyl)phenylsulphonyl-D,L-asparticacid diethyl ester

EXAMPLE 23

N-Methyl-N-4-(1H-2-butyl-4-chloro-5-hydroxymethylimidazolylmethyl)phenylsulphonyl-L-leucineethyl ester ##STR13## 2-Butyl-4-chloro-5-hydroxymethylimidazole (1.50 g,8 mmol) was dissolved in dry methanol (20 ml) under argon and sodiumwire (184 mg, 8 mmol) was added. The reaction mixture was stirred atroom temperature for 0.5 h and the solvent removed under reducedpressure. The residue was dissolved in dry DMF (40 ml) under argon and asolution of N-methyl-N-4-bromomethylphenylsulphonyl-L-leucine ethylester (3.25 g, 8 mmol) in DMF (5 ml) was added. The mixture was stirredovernight at 50° C. and evaporated to dryness and the residuepartitioned between ethyl acetate and aqueous ammonium chloride. Theorganic extracts were washed with brine, dried over anhydrous sodiumsulphate, filtered and evaporated. Column chromatography (silica: 3%methanol in DCM) gaveN-methyl-N-4-(1H-2-butyl-4-chloro-5-hydroxymethylimidazolylmethyl)phenylsulphonyl-L-leucineethyl ester (670 mg, 35%) as an off-white foam.

Analysis calculated for C₂₄ H₃₆ ClN₃ O₅ S Requires C 56.07 H 7.06 N 8.17Found C 55.86 H 7.05 N 8.19

i.r. (CDCl₃) 3600, 2960, 2220, 1735, 1340, 1255, 1150 cm⁻¹

delta_(H) 7.70 (2H, d, J 8.3 Hz), 7.09 (2H, d, J 8.3 Hz), 5.27 (2H, s),4.60 (1H, t, J 8.0 Hz), 4.40 (2H, br s), 3.94 (1H, br s), 3.86 (2H, q, J7.1 Hz), 2.79 (3H, s), 2.46 (2H, dd, J 7.4, 7.4 Hz), 1.63-1.51 (5H, m),1.34-1.22 (2H, m), 1.06 (3H, t, J 7.1 Hz), 0.93 (3H, d, J 6.0 Hz), 0.91(3H, d, J 6.0 Hz), 0.82 (3H, t, J 7.3 Hz).

EXAMPLE 24

N-Methyl-N-4-(1H-2-butyl-4-chloro-5-hydroxymethylimidazolylmethyl)phenylsulphonyl-L-leucinen-propyl ester ##STR14##N-Methyl-N-4-(1H-2-butyl-4-chloro-5-hydroxymethylimidazolylmethyl)phenylsulphonyl-L-leucinen-propyl ester was prepared by the procedure of Example 23 employingN-methyl-N-4-bromomethylphenylsulphonyl-L-leucine n-propyl ester in lieuof N-methyl-N-4-bromomethylphenylsulphonyl-L-leucine ethyl ester.N-Methyl-N-4-bromomethylphenylsulphonyl-L-leucine n-propyl ester wasprepared by the procedue of Example 1 Step (b) and Example 2 Step (a)employing L-leucine n-propyl ester hyrochloride as starting material.

Pale yellow solid (35% yield after chromatography (silica: 0-5% methanolin chloroform)): m.p. 36°-43° C

Analysis calculated for C₂₅ H₃₈ N₃ ClO₅ S Requires C 56.86 H 7.25 N 7.96Found C 56.53 H 7.01 N 8.14

i.r. (nujol) 3540, 3200, 1730, 1600, 1545, 1250, 1146, 720 cm⁻¹

delta_(H) 7.78 (2H, d, J 8.5 Hz), 7.12 (2H, d, J 8.5 Hz), 5.28 (2H, s),4.68 (1H, t, J 7.8 Hz), 4.48 (2H, s), 3.87 (2H, dt, J 3.6, 2.2 Hz), 2.84(3H, s), 2.56 (2H, t, J 7.5 Hz), 1.60-1.20 (9H, m), 1.10-0.85 (12H, m).

EXAMPLES 25-42

The compounds of Examples 25-42 may be prepared by the procedure ofExample 24 employing the appropiate amino acid derivative in lieu ofL-leucine n-propyl ester hyrochloride as starting material.

25.N-Methyl-N-4-(1H-2-butyl-4-chloro-5-hydroxymethylimidazolylmethyl)phenylsulphonylglycinemethyl ester

26.N-Methyl-N-4-(1H-2-butyl-4-chloro-5-hydroxymethylimidazolylmethyl)phenylsulphonyl-2,2-dimethylglycinemethyl ester

27.N-Methyl-N-4-(1H-2-butyl-4-chloro-5-hydroxymethylimidazolylmethyl)phenylsulphonyl-1-methoxycarbonyIcyclohexylamine

28.N-Methyl-N-4-(1H-2-butyl-4-chloro-5-hydroxymethylimidazolylmethyl)phenylsulphonyl-D,L-alaninemethyl ester

29.N-Ethyl-N-4-(1H-2-butyl-4-chloro-5-hydroxymethylimidazolylmethyl)phenylsulphonyl-D-phenylalaninemethyl ester

30.N-Ethyl-N-4-(1H-2-butyl-4-chloro-5-hydroxymethylimidazolylmethyl)phenylsulphonyl-L-phenylalaninemethyl ester

31.N-Methyl-N-4-(1H-2-butyl-4-chloro-5-hydroxymethylimidazolylmethyl)phenylsulphonyl-L-valinemethyl ester

32.N-Methyl-N-4-(1H-2-butyl-4-chloro-5-hydroxymethylimidazolylmethyl)phenylsulphonyl-D-valinemethyl ester

33.N-Methyl-N-4-(1H-2-butyl-4-chloro-5-hydroxymethylimidazolylmethyl)phenylsulphonyl-D,L-t-butylglycinemethyl ester

34.N-Methyl-N-4-(1H-2-butyl-4-chloro-5-hydroxymethylimidazolylmethyl)phenylsulphonyl-D-leucineethyl ester

35.N-n-Propyl-N-4-(1H-2-butyl-4-chloro-5-hydroxymethylimidazolylmethyl)phenylsulphonyl-L-isoleucineethyl ester

36.N-n-Propyl-N-4-(1H-2-butyl-4-chloro-5-hydroxymethylimidazolylmethyl)phenylsulphonyl-D-isoleucineethyl ester

37.N-Methyl-N-4-(1H-2-butyl-4-chloro-5-hydroxymethylimidazolylmethyl)phenylsulphonyl-D,L-norleucineethyl ester

38.N-Methyl-N-4-(1H-2-butyl-4-chloro-5-hydroxymethylimidazolylmethyl)phenylsulphonyl-O-methyl-L-tyrosinemethyl ester

39.N-Methyl-N-4-(1H-2-butyl-4-chloro-5-hydroxymethylimidazolylmethyl)phenylsulphonyl-O-methyl-D-tyrosinemethyl ester

40.N-Methyl-N-4-(1H-2-butyl-4-chloro-5-hydroxymethylimidazolylmethyl)phenylsulphonyl-O-benzyl-D,L-serinemethyl ester

41.N-Methyl-N-4-(1H-2-butyl-4-chloro-5-hydroxymethylimidazolylmethyl)phenylsulphonyl-D,L-methioninemethyl ester

42.N-Methyl-N-4-(1H-2-butyl-4-chloro-5-hydroxymethylimidazolylmethyl)phenylsulphonyl-D,L-asparticacid diethyl ester

EXAMPLES 43 and 44

The compounds of Examples 43 and 44 were prepared fromN-methyl-N-4-bromomethylphenylsulphonyl-L-leucine ethyl ester by theprocedure of Example 23 employing the appropriate imidazole derivativein lieu of 2-butyl-4-chloro-5-hydroxymethylimidazole and methanol as aco-solvent to achieve transesterification.

43. N-Methyl-N-4-(1H-2-ethylimidazolylmethyl)phenylsulphonyl-L-leucinemethyl ester ##STR15##

Colourless oil (91% yield after chromatography (2-5% methanol in DCM)):

i.r. (CDCl₃) 2960, 2200, 1740, 1340, 1150 cm⁻¹

delta_(H) 7.74 (2H, d, J 8.5 Hz), 7.13 (2H, d, J 8.6 Hz), 7.01 (1H, d, J1.2 Hz), 6.83 (1H, d, J 1.4 Hz), 5.13 (2H, s), 4.68-4.61 (1H, m), 3.43(3H, s), 2.82 (3H, s), 2.59 (2H, q, J 7.5 Hz), 1.65-1.55 (3H, m), 1.27(3H, t, J 7.5 Hz), 0.94 (3H, d, 6.0 Hz), 0.93 (3H, d, J 6.1 Hz);

delta_(C) 171.29, 149.43, 141.38, 138.63, 127.90, 127.66, 126.72,119.69, 56.96, 51.64, 48.70, 37.99, 29.72, 24.31, 22.94, 21.01, 20.02,11.83.

44.N-Methyl-N-4-(1H-2-n-propylimidazolylmethyl)phenylsulphonyl-L-leucinemethyl ester ##STR16##

Colourless oil (51% yield after chromatography (2-4% methanol in DCM)):

Analysis calculated for C₂₁ H₃₁ N₃ O₄ S Requires C 59.83 H 7.41 N 9.97Found C 60.04 H 7.44 N 9.95

i.r. (CDCl₃) 2960, 2200, 1740, 1600, 1410, 1345 cm⁻¹

delta_(H) 7.64 (2H, d, J 8.2 Hz), 7.06 (2H, d, J 8.1 Hz), 6.90 (1H, s),6.75 (1H, s), 5.07 (2H, s), 4.59-4.53 (1H, m), 3.34 (3H, s), 2.73 (3H,s), 2.46 (2H, t, J 7.6 Hz), 1.63 (2H, q, J 7.5 Hz), 1.55-1.50 (3H, m),0.87-0.81 (9H, m).

EXAMPLE 45

(A) N-4-(3H-Imidazo 4,5-b!pyridylmethyl)phenylsulphonyl-L-leucinyl ethylether and (B) N-4-(1H-imidazo4,5-b!pyridylmethyl)phenylsulphonyl-L-leucinyl ethyl ether ##STR17##

(A) N-4-(3H-Imidazo 4,5-b!pyridylmethyl)phenylsulphonyl-L-leucinyl ethylether and (B) N-4-(1H-imidazo4,5-b!pyridylmethyl)phenylsulphonyl-L-leucinyl ethyl ether were preparedby the procedure of Example 1 Step (c) employing imidazo 4,5-b!pyridinein lieu of 2-phenylimidazole andN-4-bromomethylphenylsulphonyl-L-leucinyl ethyl ether in lieu ofN-4-bromomethylphenylsulphonyl-L-leucine ethyl ester. The tworegioisomers were separated by chromatography (silica: 5% methanol inDCM) eluting in the order:

Regioisomer (A): Colourless oil (15% yield):

Analysis calculated for C₂₁ H₂₈ N₄ O₃ S .0.8H₂ O Requires C 58.53 H 6.92N 13.00 Found C 58.41 H 6.57 N 12.88

i.r. (CDCl₃) 1600, 1330, 1155 cm⁻¹

delta_(H) 8.42 (1H, dd, J 4.8, 1.3 Hz), 8.17-8.10 (2H, m), 7.85 (2H, d,J 8.3 Hz), 7.42 (2H, d, J 8.3 Hz), 7.29 (1H, dd, J 7.9, 4.8 Hz), 5.57(2H, s), 4.81 (1H, d, J 8.6 Hz), 3.43-3.10 (5H, m), 1.60-1.19 (3H, m),1.00 (3H, t, J 6.9 Hz), 0.79 (3H, d, J 6.6 Hz), 0.71 (3H, d, J 6.5 Hz).

Regioisomer (B): Colourless oil (15% yield):

Analysis calculated for C₂₁ H₂₈ N₄ O₃ S .0.8H₂ O Requires C 58.53 H 6.92N 13.00 Found C 58.63 H 6.57 N 13.02

i.r. (CDCl₃) 1610, 1330, 1150 cm⁻¹

delta_(H) 8.52 (1H, dd, J 4.8, 1.4 Hz), 8.25 (1H, s), 7.80 (2H, d, J 8.3Hz), 7.50 (1H, dd, J 8.2, 1.5 Hz), 7.24 (2H, d, J 8.3 Hz), 7.12 (1H, d,J 8.2, 4.8 Hz), 5.46 (2H, s), 5.33 (1H, d, J 8.5 Hz), 3.42-3.27 (1H, m),3.29-3.08 (4H, m), 1.60-1.16 (3H, m), 0.95 (3H, t, J 6.9 Hz), 0.74 (3H,d, J 6.6 Hz), 0.67 (3H, d, J 6.5 Hz).

EXAMPLES 46-81

The compounds of Examples 46-81 may be prepared either by the procedureof Example 5 or by the procedure of Example 45 employing the appropriateheterocycle as starting material.

46. N-4-(1H-2-n-Propylpyrrolo2,3-b!pyridinylmethyl)phenylsulphonylglycine methyl ester

47.N-4-(2H-3-n-Propylisoquinol-1-onylmethyl)phenylsulphonyl-2,2-dimethylglycinemethyl ester

48. N-4-(3H-2-n-Butyl-5-methylthieno2,3-d!pyrimidin-4-onylmethyl)phenylsulphonyl-1-methoxycarbonylcyclohexylamine

49. N-4-(3H-2-n-Butyl-6-methyl-5-phenylimidazo1,2-b!-1,2,4-triazolylmethyl)phenylsulphonyl-D,L-alanine methyl ester

50. N-4-(1H-4-Chloro-2,6-dimethylpyrrolo3,2-c!pyridinylmethyl)phenylsulphonyl-L-phenylalanine methyl ester

51. N-4-(1H-4-Chloro-2,6-dimethylpyrrolo3,2-c!pyridinylmethyl)phenylsulphonyl-D-phenylalanine methyl ester

52.N-4-(7H-8-n-Butyl-3,7-dihydro-1,3-dimethylpurine-2,6-dionylmethyl)phenylsulphonyl-L-phenylalaninemethyl ester

53.N-4-(7H-8-n-Butyl-3,7-dihydro-1,3-dimethylpurine-2,6-dionylmethyl)phenylsulphonyl-D-phenylalaninemethyl ester

54. N-4-(1H-3,5-Dibutyl-1,2,4-triazolylmethyl)phenylsulphonyl-L-valinemethyl ester

55. N-4-(1H-3,5-Dibutyl-1,2,4-triazolylmethyl)phenylsulphonyl-D-valinemethyl ester

56.N-4-(3H-2-n-Butyl-6-(1-hydroxy-1-methyIethyl)quinazolin-4-onylmethyl)phenylsulphonyl-D,L-t-butylglycinemethyl ester

57. N-4-(7H-2,4-Dimethyl-5,7-dihydropyrrolo2,3-d!pyrimidin-6-onylmethyl)phenylsulphonyl-L-leucine ethyl ester

58. N-4-(7H-2,4-Dimethyl-5,7-dihydropyrrolo2,3-d!pyrimidin-6-onylmethyl)phenylsulphonyl-D-leucine ethyl ester

59.N-4-(1H-2-n-Propyl-4-chloro-5-formylimidazolylmethyl)phenylsulphonyl-L-isoleucineethyl ester

60.N-4-(1H-2-n-Propyl-4-chloro-5-formylimidazolylmethyl)phenylsulphonyl-D-isoleucineethyl ester

61. N-Methyl-N-4-(3H-2-ethyl-5,7-dimethylimidazo4,5-b!pyridinylmethyl)phenylsulphonylglycine methyl ester

62. N-Methyl-N-4-(3H-2-ethyl-5,7-dimethylimidazo4,5-b!pyridinylmethyl)phenylsulphonyl-2,2-dimethylglycine methyl ester

63. N-Methyl-N-4-(3H-2-ethyl-5,7-dimethylimidazo4,5-b!pyridinylmethyl)phenylsulphonyl-1-methoxycarbonylcyclohexylamine

64. N-Methyl-N-4-(3H-2-ethyl-5,7-dimethylimidazo4,5-b!pyridinylmethyl)phenylsulphonyl-D,L-alanine methyl ester

65. N-4-(3H-2-Ethyl-5,7-dimethylimidazo4,5-b!pyridinylmethyl)phenylsulphonyl-D,L-alanine methyl ester

66. N-Methyl-N-4-(3H-2-ethyl-5,7-dimethylimidazo4,5-b!pyridinylmethyl)phenylsulphonyl-D,L-alanine methyl ester

67.N-Methyl-N-4-(4H-3-ethylthio-1,2,4-benzothiadiazinedioxidemethyl)phenylsulphonyl-D-phenylalaninemethyl ester

68.N-Methyl-N-4-(4H-3-ethylthio-1,2,4-benzothiadiazinedioxidemethyl)phenylsulphonyl-L-phenylalaninemethyl ester

69.N-Methyl-N-4-(4H-3-n-butyl-5-(4-chlorobenzylthio)-1,2,4-triazolylmethyl)phenylsulphonyl-L-valinemethyl ester

70.N-Methyl-N-4-(4H-3-n-butyl-5-(4-chlorobenzylthio)-1,2,4-triazolylmethyl)phenylsulphonyl-D-valinemethyl ester

71.N-Methyl-N-4-(1H-2-n-butyl-4-chloro-1,6-dihydro-5-hydroxycarbonyl-6-methylpyrimidinylmethyl)phenylsulphonyl-D,L-t-butylglycinemethyl ester

72.N-Methyl-N-4-(1H-2-n-butyl-4-trifluoromethyl-5-hydroxycarbonylimidazolylmethyl)phenylsulphonyl-D-leucineethyl ester

73.N-Methyl-N-4-(1H-2-n-butyl-4-trifluoromethyl-5-hydroxycarbonylimidazolylmethyl)phenylsulphonyl-L-leucineethyl ester

74.N-Methyl-N-4-(3H-2-ethylpyrimidin-4-onylmethyl)phenylsulphonyl-L-isoleucineethyl ester

75.N-Methyl-N-4-(3H-2-ethylpyrimidin-4-onylmethyl)phenylsulphonyl-D-isoleucineethyl ester

76.N-Methyl-N-4-(1H-2-n-propylpyrrolylmethyl)phenylsulphonyl-D,L-norleucineethyl ester

77. N-Methyl-N-4-(3H-2-n-butyl-6-methylpyrido2,3-d!pyrimidin-4-onylmethyl)phenylsulphonyl-O-methyl-L-tyrosine methylester

78. N-Methyl-N-4-(3H-2-n-butyl-6-methylpyrido2,3-d!pyrimidin-4-onylmethyl)phenylsulphonyl-O-methyl-D-tyrosine methylester

79.N-Methyl-N-4-(1H-3-n-butyl-1,4-dihydo-4-thioxoquinolinylmethyl)phenylsulphonyl-O-benzyl-D,L-serinemethyl ester

80.N-Methyl-N-4-(1H-2-n-butyl-4-chloro-5-(3-methyl-1,2,4-oxadiazol-5-yl)imidazolylmethyl)-phenylsuIphonyl-D,L-methioninemethyl ester

81.N-Methyl-N-4-(1H-2-n-butyl-4-spirocyclopentane-2-imidazoline-5-onylmethyl)phenylsulphonyl-D,L-asparticacid diethyl ester

EXAMPLE 82

N-Methyl-N-4-(9H-2,6-dichloropurinylmethyl)phenylsulphonyl-L-leucinen-propyl ester ##STR18##N-Methyl-N-4-(9H-2,6-dichloropurinylmethyl)phenylsulphonyl-L-leucinen-propyl ester was prepared by the procedure of Example 23 employing2,6-dichloropurine in lieu of 2-butyl-4-chloro-5-hydroxymethylimidazoleand N-methyl-N-4-bromomethylphenylsulphonyl-L-leucine n-propyl ester inlieu of N-methyl-N-4-bromomethylphenylsulphonyl-L-leucine ethyl ester.

Colourless viscous oil (24% yield after chromatography (silica: 0-2%methanol in DCM)):

i.r. (CHCl₃) 3680, 2960, 2870, 1730, 1595, 1565, 1350, 1170, 1150, 880cm⁻¹

delta_(H) 8.10 (1H, s), 7.82 (2H, d, J 8.3 Hz), 7.41 (2H, d, J 8.3 Hz),5.49 (2H, s), 4.67 (1H, br t), 3.85 (2H, t, J 6.5 Hz), 2.83 (3H, s),1.63-0.84 (14H, m);

delta_(C) 170.94, 145.43, 138.64, 128.25, 128.12, 64.86, 57.25, 46.26,38.12, 30.33, 29.79, 24.41, 22.99, 21.16, 18.96.

EXAMPLE 83

N-4-(1H-Imidazolylmethyl)phenylsulphonyl-L-leucinyl t-butyldiphenylsilylether ##STR19## (a) N-4-Bromomethylphenylsulphonyl-L-leucinol

N-4-Bromomethylphenylsulphonyl-L-leucinol was prepared by the method ofExample 1 Step (b) employing L-leucinol in lieu of L-leucine ethyl esterhydrochloride.

Colourless oil: (37% yield after chromatography (silica: 50% ethylacetate in hexane).

delta_(H) 7.91 (2H, d, J 8.3 Hz), 7.53 (2H, d, J 8.4 Hz), 5.31 (1H, d, J7.7 Hz), 4.62 (2H, s), 3.62-3.44 (2H, m), 3.36-3.27 (1H, m), 2.60 (1H,br s), 1.45-1.37 (1H, m), 1.25 (2H, t, J 7.2 Hz), 0.76 (3H, d, J 6.5Hz), 0.62 (3H, d, J 6.4 Hz).

(b) N-4-Bromomethylphenylsulphonyl-L-leucinyl 2-t-butyldiphenylsilylether

2-t-Butyldiphenylsilyl chloride (12.3 ml, 47.1 mmol) and4-dimethylaminopyridine (10 mg) were added to a solution ofN-4-bromomethylphenylsulphonyl-L-leucinol (15.0 g, 42.9 mmol) anddiisopropylethylamine (37.3 ml, 0.21 mol) in dry DMF (150 ml) and themixture stirred at room temperature under argon overnight. Ethyl acetatewas added and the mixture washed with aqueous ammonium chloride andbrine. The combined aqueous washings were extracted with ethyl acetateand the combined organics dried over anhydrous sodium sulphate, filteredand concentrated to give a quantitative yield of crudeN-4-bromomethylphenylsulphonyl-L-leucinyl 2-t-butyldiphenylsilyl etheras a viscous oil which was used directly in the next step.

delta_(H) 8.05-7.31 (14H, m), 4.89 (1H, d, J 10.0 Hz), 4.58 (2H, s),3.51-3.42 (2H, m), 3.40-3.23 (1H, m), 1.78-1.69 (1H, m), 1.55-1.32 (2H,m), 1.02 (9H, s), 0.77 (3H, d, J 6.6 Hz), 0.72 (3H, d, J 6.5 Hz).

(c) N-4-(1H-Imidazolylmethyl)phenylsulphonyl-L-leucinylt-butyldiphenylsilyl ether

N-4-(1H-Imidazolylmethyl)phenylsulphonyl-L-leucinylt-butyl-diphenylsilyl ether was prepared by the procedure of Example 1Step (c) employing imidazole in lieu of 2-phenylimidazole andN-4-bromomethylphenylsulphonyl-L-leucinyl 2-t-butyldiphenylsilyl etherin lieu of N-4-bromomethylphenylsulphonyl-L-leucine ethyl ester.

Amorphous white solid (20% yield after chromatography (silica: 5%methanol in DCM)):

i.r. (CDCl₃) 3380, 2910, 1590, 1400 cm⁻¹

delta_(H) 7.73 (2H, d, J 8.3 Hz), 7.60-7.47 (5H, m), 7.47-7.30 (6H, m),7.14-7.04 (3H, m), 6.79 (1H, s), 5.52 (1H, d, J 8.2 Hz), 5.12 (2H, s),3.57-3.41 (2H, m), 3.40-3.24 (1H, m), 1.55-1.36 (3H, m), 1.01 (9H, s),0.77 (3H, d, J 6.1 Hz), 0.69 (3H, d, J 6.1 Hz).

EXAMPLE 84

N-4-(1H-Imidazolylmethyl)phenylsulphonyl-L-leucinol ##STR20##

A stirred solution ofN-4-(1H-imidazolylmethyl)phenylsulphonyl-L-leucinyl t-butyldiphenylsilylether (2.2 g, 3.82 mmol) in dry THF (50 ml) was treated at 0° C. with a1M solution of tetrabutylammonium fluoride in THF (7.64 ml, 7.64 mmol).The reaction mixture was allowed to warm up to room temperature and wasstirred for 5 h. The solvent was removed under reduced pressure and theresidue purified by chromatography (silica: 5% methanol in DCM) to giveN-4-(1H-imidazolylmethyl)phenylsulphonyl-L-leucinol (0.19 g, 15%) as awhite amorphous solid.

Analysis calculated for C 16H₂₃ N₃ O₃ S Requires C 56.95 H 6.87 N 12.45Found C 57.00 H 6.92 N 12.54

i.r. (KBr) 1310, 1150, 1090 cm⁻¹

delta_(H) 7.89 (2H, d, J 8.4 Hz), 7.58 (1H, br s), 7.28 (2H, d, J 8.3Hz), 7.14 (1H, br s), 6.89 (1H, br s), 5.22 (2H, s), 4.71 (1H, d, J 7.8Hz), 3.58 (1H, dd, J 11.0, 3.7 Hz), 3.47 (1H, dd, J 11.1, 4.8 Hz),3.40-3.25 (1H, m), 1.53-1.20 (3H, m), 0.79 (3H, d, J 6.5 Hz), 0.66 (3H,d, J 6.4 Hz).

EXAMPLE 85

N-4-(1H-2-Methylimidazolylmethyl)phenylsulphonyl-L-leucinol ##STR21##(a) N-Methy-N-4-bromomethylphenylsulphonyl-L-leucinyl2-t-butyldiphenylsilyl ether

N-Methy-N-4-bromomethylphenylsulphonyl-L-leucinyl2-t-butyl-diphenylsilyl ether was prepared by the procedure of Example 2Step (a) employing N-4-bromomethylphenylsulphonyl-L-leucinyl2-t-butyldiphenylsilyl ether in lieu ofN-4-bromomethylphenylsulphonyl-L-leucine ethyl ester.

delta_(H) 7.75-7.33 (14H, m), 4.41 (2H, s), 3.76 (1H, m), 3.58-3.51 (2H,m), 2.77 (3H, s), 1.38-1.26 (1H, m), 1.05 (2H, m), 1.04 (9H, s), 0.86(3H, d, J 5.9 Hz), 0.85 (3H, d, J 6.2 Hz).

(b) N-4-(1H-2-Methylimidazolylmethyl)phenylsulphonyl-L-leucinol

A suspension of potassium hydroxide (224 mg, 4.0 mmol), TDA-1 (4 drops)in dry acetonitrile (40 ml) was stirred for 10 min. at room temperatureunder argon. 2-Methylimidazole (137 mg, 1.67 mmol) was added and thereaction mixture was heated at 80° C. for 40 min. and cooled to 40° C. Asolution of N-methyl-N-4-bromomethylphenylsulphonyl-L-leucinyl2-t-butyldiphenylsilyl ether (1.0 g, 1.67 mmol) in dry acetonitrile (15ml) was added and the reaction mixture stirred at 40° C. overnight andcooled to room temperature. Ethanol (50 ml) was added and the resultingslurry filtered through a short pad of celite. Column chromatography(silica: 5% methanol in DCM) gave the deprotected compoundN-4-(1H-2-methhylimidazolylmethyl)phenylsulphonyl-L-leucinol (0.10 g,17%) as a white crystalline solid: m.p. 157°-159° C.

Analysis calculated for C₁₈ H₂₇ N₃ O₃ S.0.3H₂ O Requires C 58.29 H 7.50N 11.33 Found C 58.35 H 7.33 N 11.33

i.r. (CDCl₃) 3620, 2960, 1600, 1405, 1330, 1195 cm⁻¹

delta_(H) 7.82 (2H, d, J 8.4 Hz), 7.13 (2H, d, J 8.2 Hz), 6.94 (1H, d, J1.3 Hz), 6.84 (1H, d, J 1.3 Hz), 5.12 (2H, s), 4.07-4.01 (1H, m),3.55-3.40 (2H, m), 2.73 (3H, s), 2.28 (3H, s), 1.46-1.38 (1H, m), 1.17(2H, t, J 7.2 Hz), 0.83 (3H, d, J 6.5 Hz), 0.81 (3H, d, J 6.4 Hz).

EXAMPLE 86

N-Methyl-N-4-(1H-2-butyl-4-chloro-5-hydroxymethylimidazolylmethyl)phenylsulphonyl-L-leucine##STR22## 2M Potassium hydroxide (1.4 ml) was added to a solution ofN-methyl-4-(1H-2-butyl-4-chloro-5-hydroxymethylimidazolylmethyl)phenylsulphonyl-L-leucineethyl ester (280 mg, 0.54 mmol) in ethanol (25 ml). The reaction mixturewas stirred at room temperature overnight. The solvent was removed underreduced pressure and water was added to the residue. The pH of theresulting solution was adjusted to pH 4 by the addition of 2M HCl. Awhite cloudy precipitate formed, which was extracted into ethyl acetate.The combined organic extracts were dried over anhydrous sodium sulphate,filtered and evaporated to giveN-methyl-N-4-(1H-2-butyl-4-chloro-5-hydroxymethylimidazolylmethyl)phenylsulphonyl-L-leucine(92 mg, 35%) as a colourless oil

i.r. (CDCl₃) 1740 cm⁻¹

delta_(H) 8.55-8.00 (1H, br s), 7.82 (2H, d, J 8.3 Hz), 7.07 (2H, d, J8.3 Hz), 5.19 (2H, s), 4.91 (2H, s), 4.74-4.63 (1H, m), 2.81 (3H, s),2.55 (2H, t, J 7.5 Hz), 1.73-1.47 (5H, m), 1.38-1.19 (2H, m), 1.00-0.89(6H, m), 0.84 (3H, t, J 7.2 Hz);

delta_(C) 169.36, 147.93, 138.80, 137.79, 128.32, 126.88, 124.80,119.30, 56.03, 52.76, 45.90, 36.65, 28.30, 25.00, 23.11, 21.73, 20.81,19.63, 19.12, 12.22.

EXAMPLES 87 AND 88

The compounds of Examples 87 and 88 were prepared by the procedure ofExample 86 employing the compounds of Examples 43 and 44 respectively inlieu ofN-methyl-4-(1H-2-butyl-4-chloro-5-hydroxymethylimidazolylmethyl)phenylsulphonyl-L-leucineethyl ester.

87. N-Methyl-N-4-(1H-2-ethylimidazolylmethyl)phenylsulphonyl-L-leucine##STR23##

Amorphous solid (3% yield after chromatography (10% methanol in DCM)):

i.r. (CDCl₃) 3960, 1715, 1335, 1150 cm⁻¹

delta_(H) 7.79 (2H, d, J 8.3 Hz), 7.35-7.32 (3H, m), 7.25 (1H, d, J 1.8Hz), 5.38 (2H, s), 4.41 (1H, t, J 7.5 Hz), 2.84 (2H, q, J 7.5 Hz), 2.81(3H, s), 1.59-1.49 (3H, m), 1.22 (3H, t, J 7.5 Hz), 0.87 (3H, d, J 6.2Hz), 0.86 (3H, d, J 6.0 Hz);

delta_(C) 177.14, 150.66, 141.04, 140.79, 129.26, 128.97, 123.08,122.26, 60.55, 50.62, 39.67, 30.53, 25.89, 23.68, 21.76, 19.88, 11.78.

88.N-Methyl-N-4-(1H-2-n-propylimidazolylmethyl)phenylsulphonyl-L-leucine##STR24##

Yellow oil (3% yield after chromatography (10% methanol in DCM)):

i.r. (CDCl₃) 3630, 3350, 2960, 2200, 1715, 1330 cm⁻¹

delta_(H) 7.79 (2H, d, J 8.3 Hz), 7.29 (2H, d, J 8.3 Hz), 7.21 (1H, d, J1.8 Hz), 7.13 (1H, d, J 1.6 Hz), 5.34 (2H, s), 4.51-4.45 (1H, m), 2.81(3H, s), 2.73 (3H, t, J 7.7 Hz), 1.68-1.50 (3H, m), 0.93-0.87 (9H, m);

delta_(C) 176.54, 149.67, 141.79, 140.62, 129.17, 128.63, 124.06,122.51, 59.97, 54.79, 39.76, 30.29, 28.38, 25.83, 23.56, 21.94, 21.62,13.88.

EXAMPLES 89-162

The compounds of Examples 89-162 may be prepared by the procedure ofExample 86 employing the appropriate ester as starting material in lieuofN-methyl-4-(1H-2-butyl-4-chloro-5-hydroxymethylimidazolylmethyl)phenylsulphonyl-L-leucineethyl ester.

89.N-4-(1H-2-Butyl-4-chloro-5-hydroxymethylimidazolylmethyl)phenylsulphonylglycine

90.N-4-(1H-2-Butyl-4-chloro-5-hydroxymethylimidazolylmethyl)phenylsulphonyl-2,2-dimethylglycine

91.N-4-(1H-2-Butyl-4-chloro-5-hydroxymethylimidazolylmethyl)phenylsulphonyl-1-aminocyclohexanecarboxylicacid

92.N-4-(1H-2-Butyl-4-chloro-5-hydroxymethylimidazolylmethyl)phenylsulphonyl-D,L-alanine

93.N-4-(1H-2-Butyl-4-chloro-5-hydroxymethylimidazolylmethyl)phenylsulphonyl-D-phenylalanine

94.N-4-(1H-2-Butyl-4-chloro-5-hydroxymethylimidazolylmethyl)phenylsulphonyl-L-phenylalanine

95.N-4-(1H-2-Butyl-4-chloro-5-hydroxymethylimidazolylmethyl)phenylsulphonyl-L-valine

96.N-4-(1H-2-Butyl-4-chloro-5-hydroxymethylimidazolylmethyl)phenylsulphonyl-D-valine

97.N-4-(1H-2-Butyl-4-chloro-5-hydroxymethylimidazolylmethyl)phenylsulphonyl-D,L-t-butylglycine

98.N-4-(1H-2-Butyl-4-chloro-5-hydroxymethylimidazolylmethyl)phenylsulphonyl-D-leucine

99.N-4-(1H-2-Butyl-4-chloro-5-hydroxymethylimidazolylmethyl)phenylsulphonyl-D-leucine

100.N-4-(1H-2-Butyl-4-chloro-5-hydroxymethylimidazolylmethyl)phenylsulphonyl-L-isoleucine

101.N-4-(1H-2-Butyl-4-chloro-5-hydroxymethylimidazolylmethyl)phenylsulphonyl-D-isoleucine

102.N-4-(1H-2-Butyl-4-chloro-5-hydroxymethylimidazolylmethyl)phenylsulphonyl-D,L-norleucine

103.N-4-(1H-2-Butyl-4-chloro-5-hydroxymethylimidazolylmethyl)phenylsulphonyl-O-methyl-L-tyrosine

104.N-4-(1H-2-Butyl-4-chloro-5-hydroxymethylimidazolylmethyl)phenylsulphonyl-O-methyl-D-tyrosine

105.N-4-(1H-2-Butyl-4-chloro-5-hydroxymethylimidazolylmethyl)phenylsulphonyl-O-benzyl-D,L-serine

106.N-4-(1H-2-Butyl-4-chloro-5-hydroxymethylimidazolylmethyl)phenylsulphonyl-D,L-methionine

107.N-4-(1H-2-Butyl-4-chloro-5-hydroxymethylimidazolylmethyl)phenylsulphonyl-D,L-asparticacid

108.N-Methyl-N-4-(1H-2-butyl-4-chloro-5-hydroxymethylimidazolylmethyl)phenylsulphonylglycine

109.N-Methyl-N-4-(1H-2-butyl-4-chloro-5-hydroxymethylimidazolylmethyl)phenylsulphonyl-2,2-dimethylglycine

110.N-Methyl-N-4-(1H-2-butyl-4-chloro-5-hydroxymethylimidazolylmethyl)phenylsulphonyl-1-aminocyclohexanecarboxylicacid

111.N-Methyl-N-4-(1H-2-butyl-4-chloro-5-hydroxymethylimidazolylmethyl)phenylsulphonyl-D,L-alanine

112.N-Ethyl-N-4-(1H-2-butyl-4-chloro-5-hydroxymethylimidazolylmethyl)phenylsulphonyl-D-phenylalanine

113.N-Ethyl-N-4-(1H-2-butyl-4-chloro-5-hydroxymethylimidazolylmethyl)phenylsulphonyl-L-phenylalanine

114.N-Methyl-N-4-(1H-2-butyl-4-chloro-5-hydroxymethylimidazolylmethyl)phenylsulphonyl-L-valine

115.N-Methyl-N-4-(1H-2-butyl-4-chloro-5-hydroxymethylimidazolylmethyl)phenylsulphonyl-D-valine

116.N-Methyl-N-4-(1H-2-butyl-4-chloro-5-hydroxymethylimidazolylmethyl)phenylsulphonyl-D,L-t-butylglycine

117.N-Methyl-N-4-(1H-2-butyl-4-chloro-5-hydroxymethylimidazolylmethyl)phenylsulphonyl-L-leucine

118.N-Methyl-N-4-(1H-2-butyl-4-chloro-5-hydroxymethylimidazolylmethyl)phenylsulphonyl-D-leucine

119.N-n-Propyl-N-4-(1H-2-butyl-4-chloro-5-hydroxymethylimidazolylmethyl)phenylsulphonyl-L-isoleucine

120.Non-Propyl-N-4-(1H-2-butyl-4-chloro-5-hydroxymethylimidazolylmethyl)phenylsulphonyl-D-isoleucine

121.N-Methyl-N-4-(1H-2-butyl-4-chloro-5-hydroxymethylimidazolylmethyl)phenylsulphonyl-D,L-norleucine

122.N-Methyl-N-4-(1H-2-butyl-4-chloro-5-hydroxymethylimidazolylmethyl)phenylsulphonyl-O-methyl-L-tyrosine

123.N-Methyl-N-4-(1H-2-butyl-4-chloro-5-hydroxymethylimidazolylmethyl)phenylsulphonyl-O-methyl-D-tyrosine

124.N-Methyl-N-4-(1H-2-butyl-4-chloro-5-hydroxymethylimidazolylmethyl)phenylsulphonyl-O-benzyl-D,L-serine

125.N-Methyl-N-4-(1H-2-butyl-4-chloro-5-hydroxymethylimidazolylmethyl)phenylsulphonyl-D,L-methionine

126.N-Methyl-N-4-(1H-2-butyl-4-chloro-5-hydroxymethylimidazolylmethyl)phenylsulphonyl-D,L-asparticacid

127. N-4-(1H-2-n-Propylpyrrolo2,3-b!pyridinylmethyl)phenylsulphonylglycine

128.N-4-(2H-3-n-Propylisoquinol-1-onylmethyl)phenylsulphonyl-2,2-dimethylglycine

129. N-4-(3H-2-n-Butyl-5-methylthieno2,3-d!pyrimidin-4-onylmethyl)phenylsulphonyl-1-aminocyclohexanecarboxylicacid

130. N-4-(3H-2-n-Butyl-6-methyl-5-phenylimidazo1,2-b!-1,2,4-triazolylmethyl)phenylsulphonyl-D,L-alanine

131. N-4-(1H-4-Chloro-2,6-dimethylpyrrolo3,2-c!pyridinylmethyl)phenylsulphonyl-L-phenylalanine

132. N-4-(1H-4-Chloro-2,6-dimethylpyrrolo3,2-c!pyridinylmethyl)phenylsulphonyl-D-phenylalanine

133.N-4-(7H-8-n-Butyl-3,7-dihydro-1,3-dimethylpurine-2,6-dionylmethyl)phenylsulphonyl-L-phenylalanine

134.N-4-(7H-8-n-Butyl-3,7-dihydro-1,3-dimethylpurine-2,6-dionylmethyl)phenylsulphonyl-D-phenylalanine

135. N-4-(1H-3,5-Dibutyl-1,2,4-triazolylmethyl)phenylsulphonyl-L-valine

136. N-4-(1H-3,5-Dibutyl-1,2,4-triazolylmethyl)phenylsulphonyl-D-valine

137.N-4-(3H-2-n-Butyl-6-(1-hydroxy-1-methylethyl)quinazolin-4-onylmethyl)phenylsulphonyl-D,L-t-butylglycine

138. N-4-(7H-2,4-Dimethyl-5,7-dihydropyrrolo2,3-d!pyrimidin-6-onylmethyl)phenylsulphonyl-L-leucine

139. N-4-(7H-2,4-Dimethyl-5,7-dihydropyrrolo2,3-d!pyrimidin-6-onylmethyl)phenylsulphonyl-D-leucine

140.N-4-(1H-2-n-Propyl-4-chloro-5-formylimidazolylmethyl)phenylsulphonyl-L-isoleucine

141.No4-(1H-2-n-Propyl-4-chloro-5-formylimidazolylmethyl)phenylsulphonyl-D-isoleucine

142. N-Methyl-N-4-(3H-2-ethyl-5,7-dimethylimidazo4,5-b!pyridinylmethyl)phenylsulphonylglycine

143. N-Methyl-N-4-(3H-2-ethyl-5,7-dimethylimidazo4,5-b!pyridinylmethyl)phenylsulphonyl-2,2-dimethylglycine

144. N-Methyl-N-4-(3H-2-ethyl-5,7-dimethylimidazo4,5-b!pyridinylmethyl)phenylsulphonyl-1-aminocyclohexanecarboxylic acid

145. N-Methyl-N-4-(3H-2-ethyl-5,7-dimethylimidazo4,5-b!pyridinylmethyl)phenylsulphonyl-D,L-alanine

146. N-4-(3H-2-Ethyl-5,7-dimethylimidazo4,5-b!pyridinylmethyl)phenylsulphonyl-D,L-alanine

147. N-Methyl-N-4-(3H-2-ethyl-5,7-dimethylimidazo4,5-b!pyridinylmethyl)phenylsulphonyl-D,L-alanine

148.N-Methyl-N-4-(4H-3-ethylthio-1,2,4-benzothiadiazinedioxidemethyl)phenylsulphonyl-D-phenylalanine

149.N-Methyl-N-4-(4H-3-ethylthio-1,2,4-benzothiadiazinedioxidemethyl)phenylsulphonyl-L-phenylalanine

150.N-Methyl-N-4-(4H-3-n-butyl-5-(4-chlorobenzylthio)-1,2,4-triazolylmethyl)phenylsulphonyl-L-valine

151.N-Methyl-N-4-(4H-3-n-butyl-5-(4-chlorobenzylthio)-1,2,4-triazolylmethyl)phenylsulphonyl-D-valine

152.N-Methyl-N-4-(1H-2-n-butyl-4-chloro-1,6-dihydro-5-hydroxycarbonyl-6-methylpyrimidinylmethyl)phenylsulphonyl-D,L-t-butylglycine

153.N-Methyl-N-4-(1H-2-n-butyl-4-trifluoromethyl-5-hydroxycarbonylimidazolylmethyl)phenylsulphonyl-D-leucine

154.N-Methyl-N-4-(1H-2-n-butyl-4-trifluoromethyl-5-hydroxycarbonylimidazolylmethyl)phenylsulphonyl-L-leucine

155.N-Methyl-N-4-(3H-2-ethylpyrimidin-4-onylmethyl)phenylsulphonyl-L-isoleucine

156.N-Methyl-N-4-(3H-2-ethylpyrimidin-4-onylmethyl)phenylsulphonyl-D-isoleucine

157.N-Methyl-N-4-(1H-2-n-propylpyrrolylmethyl)phenylsulphonyl-D,L-norleucine

158. N-Methyl-N-4-(3H-2-n-butyl-6-methylpyrido2,3-d!pyrimidin-4-onylmethyl)phenylsulphonyl-O-methyl-L-tyrosine

159. N-Methyl-N-4-(3H-2-n-butyl-6-methylpyrido2,3-d!pyrimidin-4-onylmethyl)phenylsulphonyl-O-methyl-D-tyrosine

160.N-Methyl-N-4-(1H-3-n-butyl-1,4-dihydo-4-thioxoquinolinylmethyl)phenylsulphonyl-O-benzyl-D,L-serine

161.N-Methyl-N-4-(1H-2-n-butyl-4-chloro-5-(3-methyl-1,2,4-oxadiazol-5-yl)imidazolylmethyl)-phenylsulphonyl-D,L-methionine

162.N-Methyl-N-4-(1H-2-n-butyl-4-spirocyclopentane-2-imidazoline-5-onylmethyl)phenylsulphonyl-D,L-asparticacid

EXAMPLES 163-176

The carboxylic acid derivatives of Examples 89-162 may be converted tothe corresponding tetrazoles by standard literature protocols such asthat described by J. V. Duncia, M. E. Pierce and J. B. Santella III, J.Org. Chem., 1991, 56, 2395-2400.

163.N-4-(1H-2-Butyl-4-chloro-5-hydroxymethylimidazolylmethyl)phenylsulphonyl-1-(1H-tetrazol-5-yl)methylamine

164.N-Methyl-N-4-(1H-2-butyl-4-chloro-5-hydroxymethylimidazolylmethyl)phenylsulphonyl-1-methyl-1-(1H-tetrazol-5-yl)ethylamine

165.N-Methyl-N-4-(1H-2-butyl-4-chloro-5-hydroxymethylimidazolylmethyl)phenylsulphonyl-1-(1H-tetrazol-5-yl)cyclohexylamine

166.(S)-N-4-(1H-3,5-Dibutyl-1,2,4-triazolylmethyl)phenylsulphonyl-2-methyl-1-(1H-tetrazol-5-yl)propylamine

167.(R)-N-4-(1H-3,5-Dibutyl-1,2,4-triazolylmethyl)phenylsulphonyl-2-methyl-1-(1H-tetrazol-5-yl)propylamine

168.(S)-N-4-(1H-2-Butyl-4-chloro-5-formylimidazolylmethyl)phenylsulphonyl-2-methyl-1-(1H-tetrazol-5-yl)butylamine

169.(R)-N-4-(1H-2-Butyl-4-chloro-5-formylimidazolylmethyl)phenylsulphonyl-2-methyl-1-(1H-tetrazol-5-yl)butylamine

170.N-Methyl-N-4-(1H-2-n-butyl-4-chloro-1,6-dihydro-5-hydroxycarbonyl-6-methylpyrimidinylmethyl)phenylsulphonyl-2,2-dimethyl-1-(1H-tetrazol-5-yl)propylamine171.N-Methyl-N-4-(1H-2-butyl-4-chloro-5-hydroxymethylimidazolylmethyl)phenylsulphonyl-1-(1H-tetrazol-5-yl)ethylamine

172.(S)-N-Ethyl-N-4-(1H-2-butyl-4-chloro-5-hydroxymethylimidazolylmethyl)phenylsulphonyl-1-phenyl-1-(1H-tetrazol-5-yl)methylamine

173.(R)-N-Ethyl-N-4-(1H-2-butyl-4-chloro-5-hydroxymethylimidazolylmethyl)phenylsulphonyl-1-phenyl-1-(1H-tetrazol-5-yl)methylamine

174.(S)-N-Methyl-N-4-(1H-2-butyl-4-chloro-5-hydroxymethylimidazolylmethyl)phenylsulphonyl-1-methyl-1-(1H-tetrazol-5-yl)ethylamine

175.(R)-N-Methyl-N-4-(1H-2-butyl-4-chloro-5-hydroxymethylimidazolylmethyl)phenylsulphonyl-1-methyl-1-(1H-tetrazol-5-yl)ethylamine

176.N-Methyl-N-4-(1H-2-butyl-4-chloro-5-hydroxymethylimidazolylmethyl)phenylsulphonyl-2,2-dimethyl-1-(1H-tetrazol-5-yl)propylamine

EXAMPLES 177-203

The carboxylic acid derivatives of Examples 89-162 may be converted tothe corresponding amide derivatives by standard literature protocols.

177.N-4-(1H-2-Butyl-4-chloro-5-hydroxymethylimidazolylmethyl)phenylsulphonylglycine1H-tetrazol-5-ylamide

178.N-4-(1H-2-Butyl-4-chloro-5-hydroxymethylimidazolylmethyl)phenylsulphonyl-2,2-dimethylglycine1H-tetrazol-5-ylamide.

179.N-4-(1H-2-Butyl-4-chloro-5-hydroxymethylimidazolylmethyl)phenylsulphonyl-D,L-alanine1H-tetrazol-5-ylamide

180.N-4-(1H-2-Butyl-4-chloro-5-hydroxymethylimidazolylmethyl)phenylsulphonyl-D-phenylalanine1H-tetrazol-5-ylamide

181.N-4-(1H-2-Butyl-4-chloro-5-hydroxymethylimidazolylmethyl)phenylsulphonyl-L-phenylalanine1H-tetrazol-5-ylamide

182.N-4-(1H-2-Butyl-4-chloro-5-hydroxymethylimidazolylmethyl)phenylsulphonyl-L-valinetrifluoromethylsulphonylamide

183.N-4-(1H-2-Butyl-4-chloro-5-hydroxymethylimidazolylmethyl)phenylsulphonyl-D-valinetrifluoromethylsulphonylamide

184.N-4-(1H-2-Butyl-4-chloro-5-hydroxymethylimidazolylmethyl)phenylsulphonyl-D,L-t-butylglycine1H-tetrazol-5-ylamide

185.N-4-(1H-2-Butyl-4-chloro-5-hydroxymethylimidazolylmethyl)phenylsulphonyl-D-leucinemethylsulphonylamide

186.N-4-(1H-2-Butyl-4-chloro-5-hydroxymethylimidazolylmethyl)phenylsulphonyl-D-leucinemethylsulphonylamide

187. N-Methyl-N-4-(3H-2-ethyl-5,7-dimethylimidazo4,5-b!pyridinylmethyl)phenylsulphonylglycine 1H-tetrazol-5-ylamide

188. N-Methyl-N-4-(3H-2-ethyl-5,7-dimethylimidazo4,5-b!pyridinylmethyl)phenylsulphonyl-2,2-dimethylglycine1H-tetrazol-5-ylamide

189. N-Methyl-N-4-(3H-2-ethyl-5,7-dimethylimidazo4,5-b!pyridinylmethyl)phenylsulphonyl-D,L-alanine 1H-tetrazol-5-ylamide

190. N-4-(3H-2-Ethyl-5,7-dimethylimidazo4,5-b!pyridinylmethyl)phenylsulphonyl-D,L-alanine 1H-tetrazol-5-ylamide

191. N-Methyl-N-4-(3H-2-ethyl-5,7-dimethylimidazo4,5-b!pyridinylmethyl)phenylsulphonyl-D,L-alanine 1H-tetrazol-5-ylamide

192.N-Methyl-N-4-(4H-3-ethylthio-1,2,4-benzothiadiazinedioxidemethyl)phenylsulphonyl-D-phenylalaninetrifluoromethylsulphonylamide

193.N-Methyl-N-4-(4H-3-ethylthio-1,2,4-benzothiadiazinedioxidemethyl)phenylsulphonyl-L-phenylalaninetrifluoromethylsulphonylamide

194.N-Methyl-N-4-(1H-2-butyl-4-chloro-5-hydroxymethylimidazolylmethyl)phenylsulphonylglycine1H-tetrazol-5-ylamide

195.N-Methyl-N-4-(1H-2-butyl-4-chloro-5-hydroxymethylimidazolylmethyl)phenylsulphonyl-2,2-dimethylglycine1H-tetrazol-5-ylamide

196.N-Methyl-N-4-(1H-2-butyl-4-chloro-5-hydroxymethylimidazolylmethyl)phenylsulphonyl-D,L-alanine1H-tetrazol-5-ylamide

197.N-Ethyl-N-4-(1H-2-butyl-4-chloro-5-hydroxymethylimidazolylmethyl)phenylsulphonyl-D-phenylalanine1H-tetrazol-5-ylamide

198.N-Ethyl-N-4-(1H-2-butyl-4-chloro-5-hydroxymethylimidazolylmethyl)phenylsulphonyl-L-phenylalanine1H-tetrazol-5-ylamide

199.N-Methyl-N-4-(1H-2-butyl-4-chloro-5-hydroxymethylimidazolylmethyl)phenylsulphonyl-L-valinetrifluoromethylsulphonylamide

200.N-Methyl-N-4-(1H-2-butyl-4-chloro-5-hydroxymethylimidazolylmethyl)phenylsulphonyl-D-valinetrifluoromethylsulphonylamide

201.N-Methyl-N-4-(1H-2-butyl-4-chloro-5-hydroxymethylimidazolylmethyl)phenylsulphonyl-D,L-t-butylglycinetrifluoromethylsulphonylamide

202.N-Methyl-N-4-(1H-2-butyl-4-chloro-5-hydroxymethylimidazolylmethyl)phenylsulphonyl-L-leucine1H-tetrazol-5-ylamide

203.N-Methyl-N-4-(1H-2-butyl-4-chloro-5-hydroxymethylimidazolylmethyl)phenylsulphonyl-D-leucine1H-tetrazol-5-ylamide

EXAMPLE 204

Inhibition of ³ H!-PAF Receptor Binding

The inhibition of ³ H!-PAF binding to human platelet plasma membrane bycompounds of general formula I was determined by isotopic labelling andfiltration techniques. Platelet concentrates were obtained from ahospital blood bank. These platelet concentrates (500-2500 mi.) werecentrifuged at 800 rpm for 10 minutes in a SORVALL RC3B centrifuge toremove the red blood cells present. (The word SORVALL is a trade mark.)The supernatant was subsequently centrifuged at 3,000 rpm in a SORVALLRC3B centrifuge to pellet the platelets present. The platelet richpellets were resuspended in a minimum volume of buffer (150 mM NaCl, 10mM Tris, 2 mM EDTA, pH 7.5) and layered onto Ficoll-Paque gradients, 9ml platelet concentrate to 2 ml Ficoll, and centrifuged at 1,900 rpm for15 minutes in a SORVALL RT6000 centrifuge. This step removes theresidual red blood cells and other nonspecific material such aslymphocytes from the preparation. The platelets which form a bandbetween the plasma and the Ficoll were removed, resuspended in the abovebuffer and centrifuged at 3,000 rpm for 10 minutes in a SORVALL RT6000centrifuge. The pelleted platelets were resuspended in buffer (10 mMTris, 5 mM MgCl₂, 2 mM EDTA, pH 7.0), snap freezed in liquid N₂ andallowed to thaw slowly at room temperature in order to lyse theplatelets. The latter step was repeated at least 3 times to ensureproper lysis. The lysed platelets were centrifuged at 3,000 rpm for 10minutes in a SORVALL RT6000 centrifuge and resuspended in buffer. Thelatter step was repeated twice in order to remove any cytoplasmicproteins which may hydrolyse the platelet activating factor (PAF)receptor. The prepared platelet membranes may be stored at -70° C. Afterthawing the prepared membranes were centrifuged in a SORVALL RT6000 at3,000 rpm for 10 minutes and resuspended in assay buffer.

The assay was conducted by preparing a series of Tris-buffered solutionsof the selected antagonist of predetermined concentrations. Each ofthese solutions contained ³ H!-PAF (0.5 nM; 1-O- ³H!octadecyl-2-acetyl-sn-glycero-3-phosphoryl choline with a specificactivity of 132 Ci/mmol), unlabelled PAF (1000 nM), a known amount ofthe test antagonist, and a sufficient amount of Tris-buffer solution (10mM Tris, 5 mM MgCl₂, pH 7.0, 0.25% BSA) to make the final volume 1 ml.Incubation was initiated by the addition of 100 μg of the isolatedmembrane fraction to each of the above solutions at 0° C. Two controlsamples, one (C1) which contained all the ingredients described aboveexcept the antagonist and the other (C2) contains C1 plus a 1000-foldexcess of unlabelled PAF, were also prepared and incubatedsimultaneously with the test samples. After 1 hour incubation, eachsolution was filtered rapidly under vacuo through a WHATMAN GF/C glassfibre filter in order to separate unbound PAF from bound PAF. (The wordWHATMAN is a trade mark.) The residue in each case was rapidly washed 4times with 5 ml cold (4° C.) Tris-buffer solution. Each washed residuewas dried under vacuum on a sampling manifold and placed into vialscontaining 20 ml of OPTIPHASE MP scintillation fluid and theradioactivity counted in a liquid scintillation counter. (The wordOPTIPHASE is a trade mark.) Defining the counts for total binding withantagonist from a test sample as "TBA"; the counts for total bindingfrom the control sample C1 as "TB"; and the counts for nonspecificbinding from the control sample C2 as "NSB", the percent inhibition ofeach test antagonist can be determined by the following equation:

    % Inhibition= (TB-TBA)/SB!×100

where the specific binding SB=TB-NSB

Table 1 lists results from this assay for inhibition of ³ H!-PAFreceptor binding for illustrative examples of the compounds of thisinvention.

                  TABLE 1                                                         ______________________________________                                        Results for inhibition of  .sup.3 H!-PAF receptor binding                                 Inhibition of  .sup.3 H!-PAF                                      Example     binding IC.sub.50 nM                                              ______________________________________                                         1          7                                                                  4          5                                                                 43          5                                                                  45A        20                                                                ______________________________________                                    

EXAMPLE 205

Inhibition of Angiotensin II Induced Contraction of Rabbit Aorta

The angiotensin II receptor antagonist activity of the compounds ofgeneral formula I is demonstrated in vitro by their ability to inhibitthe contraction of rabbit aorta rings caused by angiotensin II. Male NewZealand White rabbits (2.0-2.5 kg) were killed with an overdose ofanaesthetic (sodium pentobarbitone, 60 mg/kg) followed byexsanguination. The thoracic aorta was removed and cut into rings 2-3 mmwide. The endothelium was removed by immersion of the rings in 3%deoxycholate. The rings were mounted in a 25 ml organ bath under a 3 gresting tension. Dose response curves to angiotensin II were determinedin the presence and absence of antagonists. Illustrative results fromthis assay for the inhibition of angiotensin II induced contraction ofrabbit aorta rings are shown in FIG. 1.

We claim:
 1. A compound of general formula I: ##STR25## wherein: Arepresents:a) a --VR⁶ group wherein V is --C(═O)--, --C(═O)O--, --CH₂O--, --CH₂ OC(═O)--, --C(═S)--, --CH₂ OC(═O)NH--, --C(═S)O--, --CH₂ S--,--C(═O)NHSO₂ --, --SO₂ NHC(═O)-- or --CH₂ OSiPh₂ --; andR⁶ is hydrogen,--C₁ -C₁₈ alkyl, --C₂ -C₁₈ alkenyl, --C₂ -C₁₈ alkynyl, --(C₁ -C₆alkyl)OC₁ -C₆ alkyl, --(C₁ -C₆ alkyl)SC₁ -C₆ alkyl, --(C₁ -C₆ alkyl)O(C₁-C₆ alkyl)OC₁ -C₆ alkyl, --C₃ -C₈ cycloalkyl, --C₄ -C₈ cycloalkenyl orpyridyl, (any of which may optionally be substituted with one or moresubstituents selected from halogen, hydroxyl, nitro, nitrile orcarboxyl), C₁ -C₄ perfluoroalkyl, a group --D or a --(C₁ -C₆ alkyl)ODgroup wherein D represents a group ##STR26## wherein n is an integerfrom 0 to 3, and each of R⁷ and R⁸ is independently hydrogen, --C₁ -C₆alkyl, --C₂ -C₆ alkenyl, --C₂ -C₆ alkynyl, halogen, --CN, --CO₂ H, --CO₂C₁ -C₆ alkyl, --CONH₂, --CONHC₁ -C₆ alkyl, --CON(C₁ -C₆ alkyl)₂, --CHO,--CH₂ OH, --CF₃, --OC₁ -C₆ alkyl, --SC₁ -C₆ alkyl, --SOC₁ -C₆ alkyl,--SO₂ C₁ -C₆ alkyl, --NH₂ or --NHCOMe; b) a group --CH₂ OSi(R⁶)₃ whereinR⁶ is as defined above; or c) tetrazolyl;R¹ and R² each independentlyrepresent hydrogen, halogen, --C₁ -C₆ alkyl optionally substituted byone or more halogen atoms, --C₂ -C₆ alkenyl, --C₂ -C₆ alkynyl, --(C₁ -C₆alkyl)CO₂ C₁ -C₆ alkyl, --(C₁ -C₆ alkyl)SC₁ -C₆ alkyl, --(C₁ -C₆alkyl)OC₁ -C₆ alkyl, --(C₁ -C₆ alkyl)N(C₁ -C₆ alkyl)₂, --C₃ -C₈cycloalkyl, --C₄ -C₈ cycloalkenyl, --(C₁ -C₆ alkyl)C₃ -C₈ cycloalkyl,--(C₁ -C₆ alkyl)C₄ -C₈ cycloalkenyl, --(C₁ -C₆ alkyl)OC₃ -C₈ cycloalkyl,--(C₁ -C₆ alkyl)OC₄ -C₈ cycloalkenyl, --(C₁ -C₆ alkyl)SC₃ -C₈cycloalkyl, --(C₁ -C₆ alkyl)SC₄ -C₈ cycloalkenyl, a side chain of anaturally occurring amino acid, a group --D, or a --(C₁ -C₆ alkyl)ODgroup wherein D is as defined above; or R¹ and R² together with thecarbon atom to which they are attached form a C₃ -C₈ cycloalkyl ring; R³represents hydrogen, --C₁ -C₆ alkyl, --C₂ -C₆ alkenyl, --C₂ -C₆ alkynyl,--COC₁ -C₆ alkyl, --CO₂ C₁ -C₆ alkyl, --(COC₁ -C₆ alkyl)phenyl, --(CO₂C₁ -C₆ alkyl)phenyl, --(C₁ -C₆ alkyl)OC₁ -C₆ alkyl, --(C₁ -C₆ alkyl)SC₁-C₆ alkyl, --(C₁ -C₆ alkyl)CO₂ C₁ -C₆ alkyl, --C₃ -C₈ cycloalkyl, --C₄-C₈ cycloalkenyl or a group --D wherein D is as defined above; or R¹together with R³ and the atoms to which they are attached form a 5 to 8membered nitrogen-containing heterocyclic ring; R⁴ represents hydrogen,--C₁ -C₆ alkyl, --C₂ -C₆ alkenyl, halogen, --OC₁ -C₆ alkyl, --C₁ -C₄perfluoroalkyl or --C₃ -C₈ cycloalkyl; R⁵ represents hydrogen, --C₁ -C₆alkyl, --C₂ -C₆ alkenyl, --C₂ -C₆ alkynyl, --CO₂ C₁ -C₆ alkyl, --SC₁ -C₆alkyl, --(C₁ -C₆ alkyl)SC₁ -C₆ alkyl, --(C₁ -C₆ alkyl)OC₁ -C₆ alkyl,--(C₁ -C₆ alkyl)phenyl or thiophenyl;B represents imidazolyl, pyrido 4,5-b! imidazolyl, pyrido 2, 3-b! pyrrolyl, isoquinolyl, thieno 2, 3-d!pyrimidinyl, pyrido 3, 2-c! pyrrolyl, purinyl, triazolyl, quinazolyl,pyrimidino 2, 3-d! dihydropyrrolyl, benzodioxothiadiazinyl, imidazo 1,2-b! triazolyl, pyrimidinyl, pyrrolyl, pyrido 2, 3-d! pyrimidinyl orquinolinyl group, any of the rings of which groups may be optionallysubstituted with one or more substituents selected from hydrogen,halogen, --C₁ -C₄ perfluoroalkyl, hydroxyl, carbonyl, thiocarbonyl,formyl, carboxyl, --CONH₂, --NO₂, a group --D wherein D is as definedabove, --R¹¹, --OR¹¹, --SR¹¹, --SOR¹¹, --SO₂ R¹¹, --NHR¹¹, --NR¹¹ R¹¹,--CO₂ R¹¹ or CONHR¹¹ wherein R¹¹ is --C₁ -C₆ alkyl, --C₂ -C₆ alkenyl,--C₂ -C₆ alkynl, --C₃ -C₈ cycloalkyl or C₄ -C₈ cycloalkenyl, each ofwhich is optionally substituted with one or more substituents selectedfrom halogen, hydroxyl, amino, carboxyl, --C₁ -C₄ perfluoroalkyl, --C₁-C₆ alkyl, --C₂ -C₆ alkenyl, --C₂ -C₆ alkynl, --C₃ -C₈ cycloalkyl, C₄-C₈ cycloalkenyl, --OC₁ -C₆ alkyl, --SC₁ -C₆ alkyl, tetrazol-5-yl, agroup --D wherein D is as defined above or a heteroaryl orheteroarylmethyl group; or a pharmaceutically or veterinarily acceptableacid addition salt or hydrate thereof.
 2. A compound as claimed in claim1, in which A represents a) a VR⁶ group wherein V is a --C(═O)O, --CH₂O--, --CH₂ OSiPh₂ -- or --C(═O)NHSO₂ -- group and R⁶ is as defined inclaim 1, or B) a tetrazolyl group.
 3. A compound as claimed in claim 2,wherein R⁶ represents a hydrogen atom, a --C₁ -C₆ alkyl group or a --C₁-C₄ perfluoroalkyl group.
 4. A compound as claimed in claim 1, whereinR¹ represents a hydrogen atom, a --C₁ -C₆ alkyl group, a --(C₁ -C₆alkyl)CO₂ C₁ -C₆ alkyl group, a --(C₁ -C₆ alkyl)SC₁ -C₆ alkyl group, theside chain of a naturally occurring amino acid, a group --D or a --(C₁-C₆ alkyl)OD group, wherein n represents an integer of 0 or 1, R⁷represents a hydrogen atom or a --OC₁ -C₆ alkyl group and R⁸ representsa hydrogen atom.
 5. A compound as claimed in claim 1, wherein R²represents a hydrogen atom or a --C₁ -C₆ alkyl group, or together withR¹ and the carbon atom to which they are attached forms a C₃ -C₈cycloalkyl ring.
 6. A compound as claimed in claim 1, wherein R³represents a hydrogen atom or a --C₁ -C₆ alkyl group.
 7. A compound asclaimed in claim 1, wherein R⁴ represents a hydrogen atom.
 8. A compoundas claimed in claim 1, wherein R⁵ represents a hydrogen atom.
 9. Acompound as claimed in claim 1, wherein A represents the side chain ofthe amino acid leucine and R² is a hydrogen atom.
 10. A compound asclaimed in claim 1, wherein A represents a --C(═O)OH group, a--C(═O)NHSO₂ C₁ -C₆ alkyl group, a --C(═O)NHSO₂ C₁ -C₄ perfluoroalkylgroup, a tetrazolyl group or a --C(═O)NH tetrazolyl group. 11.N-4-(1H-2-Phenylimidazolylmethyl)phenylsulphonyl-L-leucine ethylester,N-Methyl-N-4-(1H-2-nitroimidazolylmethyl)phenylsulphonyl-L-leucineethyl ester,N-4-(1H-4,5-Diphenylimidazolylmethyl)phenylsulphonyl-L-leucinyl ethylether,N-4-(1H-2-Butyl-4-chloro-5-hydroxymethylimidazolylmethyl)phenylsulphonyl-L-leucineethyl ester,N-Methyl-N-4-(1H-2-butyl-4-chloro-5-hydroxymethylimidazolymethyl)phenylsulphonyl-L-leucineethyl ester,N-Methyl-N-4-(1H-2-butyl-4-chloro-5-hydroxymethylimidazolymethyl)phenylsulphonyl-L-leucinen-propyl ester,N-Methyl-N-4-(1H-2-ethylimidazolylmethyl)phenylsulphonyl-L-leucinemethyl ester,N-Methyl-N-4-(1H-2-n-propylimidazolylmethyl)phenylsulphonyl-L-leucinemethyl ester, N-4-(3H-Imidazo4,5-b!pyridylmethyl)phenylsulphonyl-L-leucinyl ethyl ether,N-4-(1H-Imidazo 4,5-b!pyridylmethyl)phenylsulphonyl-L-leucinyl ethylether,N-Methyl-N-4-(9H-2,6-dichloropurinylmethyl)phenylsulphonyl-L-leucinen-propyl ester, N-4-(1H-Imidazolylmethyl)phenylsulphonyl-L-leucinylt-butyldiphenylsilyl ether,N-4-(1H-Imidazolylmethyl)phenylsulphonyl-L-leucinol,N-4-(1H-2-Methylimidazolylmethyl)phenylsulphonyl-L-leucinol,N-Methyl-N-4-(1H-2-butyl-4-chloro-5-hydroxymethylimidazolylmethyl)phenylsulphonyl-L-leucine,N-Methyl-N-4-(1H-2-ethylimidazolylmethyl)phenylsulphonyl-L-leucine,N-Methyl-N-4-(1H-2-n-propylimidazolylmethyl)phenylsulphonyl-L-leucine,ora salt of such a compound.
 12. A method for the treatment of diseases orphysiological conditions of humans or mammalian animals mediated byplatelet activating factor, comprising administering to the patient anamount of any of the compounds claimed in claims 1, 9, 10, or 11,effective to antagonize the effects of platelet activating factor ontarget cells responsible for such diseases or physiological conditions.13. The method of claim 12, comprising administering the compoundtogether with a pharmaceutically or veterinarily acceptable carrier. 14.A method for the treatment of diseases or physiological conditions ofhumans or mammalian animals mediated by angiotensin II, comprisingadministering to the patient an amount of any of the compounds claimedin claims 1, 9, 10 or 11, effective to antagonize the effects ofangiotensin II on target cells responsible for such diseases orphysiological conditions.
 15. The method of claim 14, comprisingadministering the compound together with a pharmaceutically orveterinarily acceptable carrier.